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1.
Immunology ; 2021 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-33454989

RESUMO

The endocrine and the immune systems interact by sharing receptors for hormones and cytokines, cross-control and feedback mechanisms. To date, no comprehensive study has assessed the impact of thyroid hormones on immune homeostasis. By studying immune phenotype (cell populations, antibody concentrations, circulating cytokines, adipokines and acute-phase proteins, monocyte-platelet interactions and cytokine production capacity) in two large independent cohorts of healthy volunteers of Western European descent from the Human Functional Genomics Project (500FG and 300BCG cohorts), we identified a crucial role of the thyroid hormone thyroxin (T4) and thyroid-stimulating hormone (TSH) on the homeostasis of lymphocyte populations. TSH concentrations were strongly associated with multiple populations of both effector and regulatory T cells, whereas B-cell populations were significantly associated with free T4 (fT4). In contrast, fT4 and TSH had little impact on myeloid cell populations and cytokine production capacity. Mendelian randomization further supported the role of fT4 for lymphocyte homeostasis. Subsequently, using a genomics approach, we identified genetic variants that influence both fT4 and TSH concentrations and immune responses, and gene set enrichment pathway analysis showed enrichment of fT4-affected gene expression in B-cell function pathways, including the CD40 pathway, further supporting the importance of fT4 in the regulation of B-cell function. In conclusion, we show that thyroid function controls the homeostasis of the lymphoid cell compartment. These findings improve our understanding of the immune responses and open the door for exploring and understanding the role of thyroid hormones in the lymphocyte function during disease.

2.
Sci Rep ; 10(1): 19023, 2020 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-33149205

RESUMO

In children, soil-transmitted helminth infections have been linked to poor nutritional status and growth retardation in association with lower levels of IGF-1. In adults, IGF-1 has an anabolic and metabolic function and is related to nutritional status. Here, we assessed the impact of helminth infection on free IGF-1 and its major binding protein, IGFBP-3, in adults. The levels of IGF-1 and IGFBP3 were measured in 1669 subjects aged ≥ 16 years, before and after receiving four rounds of albendazole 400 mg/day or matching placebo for three consecutive days. Helminth infection status was assessed by microscopy (Kato-Katz) and PCR. Serum free IGF-1 level was significantly lower in helminth-infected subjects [mean difference and 95% CI - 0.068 (- 0.103; - 0.033), P < 0.001 after adjustment for age, sex, body mass index, and fasting insulin level]. There was no difference in IGFBP-3 level between helminth infected versus non-infected subjects. In the whole study population, albendazole treatment significantly increased serum free IGF-1 level [estimate and 95% CI 0.031 (0.004; - 0.057), P = 0.024] whereas no effect was found on the IGFBP-3 level. Our study showed that helminth infection in adults is associated with lower free IGF-1 levels but not with IGFBP-3 and albendazole treatment significantly increases free IGF-1 levels in the study population.Clinical Trial Registration: https://www.isrctn.com/ISRCTN75636394 .

3.
J Immunother Cancer ; 8(2)2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32943450

RESUMO

BACKGROUND: Tumor-associated macrophages (TAMs) are key components of the tumor microenvironment (TME) in non-medullary thyroid carcinoma (TC) and neuroblastoma (NB), being associated with a poor prognosis for patients. However, little is known about how tumors steer the specific metabolic phenotype and function of TAMs. METHODS: In a human coculture model, transcriptome, metabolome and lipidome analysis were performed on TC-induced and NB-induced macrophages. The metabolic shift was correlated to functional readouts, such as cytokine production and reactive oxygen species (ROS) production, including pharmacological inhibition of metabolic pathways. RESULTS: Based on transcriptome and metabolome analysis, we observed a strong upregulation of lipid biosynthesis pathways in TAMs. Subsequently, lipidome analysis revealed that tumor-induced macrophages have an increased total lipid content and enriched levels of intracellular lipids, especially phosphoglycerides and sphingomyelins. Strikingly, this metabolic shift in lipid synthesis contributes to their protumoral functional characteristics: blocking key enzymes of lipid biosynthesis in the tumor-induced macrophages reversed the increased inflammatory cytokines and the capacity to produce ROS, two well-known protumoral factors in the TME. CONCLUSIONS: Taken together, our data show that tumor cells can stimulate lipid biosynthesis in macrophages to induce protumoral cytokine and ROS responses and advocate lipid biosynthesis as a potential therapeutic target to reprogram the TME.

4.
Nutr Metab Cardiovasc Dis ; 30(4): 616-624, 2020 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-32127340

RESUMO

BACKGROUND AND AIMS: Several studies have shown that glucagon-like peptide-1 (GLP-1) analogues can affect resting energy expenditure, and preclinical studies suggest that they may activate brown adipose tissue (BAT). The aim of the present study was to investigate the effect of treatment with liraglutide on energy metabolism and BAT fat fraction in patients with type 2 diabetes. METHODS AND RESULTS: In a 26-week double-blind, placebo-controlled trial, 50 patients with type 2 diabetes were randomized to treatment with liraglutide (1.8 mg/day) or placebo added to standard care. At baseline and after treatment for 4, 12 and 26 weeks, we assessed resting energy expenditure (REE) by indirect calorimetry. Furthermore, at baseline and after 26 weeks, we determined the fat fraction in the supraclavicular BAT depot using chemical-shift water-fat MRI at 3T. Liraglutide reduced REE after 4 weeks, which persisted after 12 weeks and tended to be present after 26 weeks (week 26 vs baseline: liraglutide -52 ± 128 kcal/day; P = 0.071, placebo +44 ± 144 kcal/day; P = 0.153, between group P = 0.057). Treatment with liraglutide for 26 weeks did not decrease the fat fraction in supraclavicular BAT (-0.4 ± 1.7%; P = 0.447) compared to placebo (-0.4 ± 1.4%; P = 0.420; between group P = 0.911). CONCLUSION: Treatment with liraglutide decreases REE in the first 12 weeks and tends to decrease this after 26 weeks without affecting the fat fraction in the supraclavicular BAT depot. These findings suggest reduction in energy intake rather than an increase in REE to contribute to the liraglutide-induced weight loss. TRIAL REGISTRY NUMBER: NCT01761318.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Adiposidade/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Metabolismo Energético/efeitos dos fármacos , Hipoglicemiantes/uso terapêutico , Incretinas/uso terapêutico , Liraglutida/uso terapêutico , Perda de Peso/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/fisiopatologia , Idoso , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Método Duplo-Cego , Feminino , Humanos , Hipoglicemiantes/efeitos adversos , Incretinas/efeitos adversos , Liraglutida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Países Baixos , Estudos Prospectivos , Fatores de Tempo , Resultado do Tratamento
5.
Sci Transl Med ; 12(524)2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31894102

RESUMO

Helminth infections induce strong type 2 and regulatory responses, but the degree of heterogeneity of such cells is not well characterized. Using mass cytometry, we profiled these cells in Europeans and Indonesians not exposed to helminths and in Indonesians residing in rural areas infected with soil-transmitted helminths. To assign immune alteration to helminth infection, the profiling was performed before and 1 year after deworming. Very distinct signatures were found in Europeans and Indonesians, showing expanded frequencies of T helper 2 cells, particularly CD161+ cells and ILC2s in helminth-infected Indonesians, which was confirmed functionally through analysis of cytokine-producing cells. Besides ILC2s and CD4+ T cells, CD8+ T cells and γδ T cells in Indonesians produced type 2 cytokines. Regulatory T cells were also expanded in Indonesians, but only those expressing CTLA-4, and some coexpressed CD38, HLA-DR, ICOS, or CD161. CD11c+ B cells were found to be the main IL-10 producers among B cells in Indonesians, a subset that was almost absent in Europeans. A number of the distinct immune profiles were driven by helminths as the profiles reverted after clearance of helminth infections. Moreover, Indonesians with no helminth infections residing in an urban area showed immune profiles that resembled Europeans rather than rural Indonesians, which excludes a major role for ethnicity. Detailed insight into the human type 2 and regulatory networks could provide opportunities to target these cells for more precise interventions.

6.
Psychol Health ; 35(2): 128-143, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31130004

RESUMO

Objective: To examine self-reported medication adherence and its association with illness perceptions, beliefs about medication and personality among thyroid cancer survivors. Methods: Individuals diagnosed with thyroid cancer between 1990 and 2008, as registered in the Eindhoven Cancer Registry, received our survey; 86% (n = 306) responded.Results: Many patients reported that they never forgot taking their medicines (n = 168; 56%), never altered the dose (n = 258; 88%), never stopped taking them (n = 291; 99%), never decided to miss a dose (n = 284; 97%) and never took less than instructed (n = 286; 97%). Fifty-two percent were classified as nonadherent; of which 14% intentional nonadherent only, 70% were nonintentional nonadherent only and 16% were both intentional and nonintentional nonadherent. Nonadherers were younger, more highly educated, more often employed, had a lower stage at diagnosis, and less often reported ≥2 comorbid conditions than adherers. Furthermore, their illness affected them more emotionally and they more often reported that their life would be impossible without their medicine. Logistic regression models showed that higher age, lower education and lower perceived necessity of medication was associated with better adherence while beliefs about medication, illness perceptions, and personality were not associated with adherence.Conclusions: Despite lifelong dependence on supplement therapy, 52% of thyroid cancer survivors were nonadherent.


Assuntos
Antineoplásicos/uso terapêutico , Sobreviventes de Câncer/psicologia , Conhecimentos, Atitudes e Prática em Saúde , Adesão à Medicação/psicologia , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/psicologia , Personalidade Tipo D , Adulto , Idoso , Sobreviventes de Câncer/estatística & dados numéricos , Feminino , Humanos , Masculino , Adesão à Medicação/estatística & dados numéricos , Pessoa de Meia-Idade , Sistema de Registros , Autorrelato
7.
J Clin Endocrinol Metab ; 105(1)2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31612224

RESUMO

BACKGROUND: Obstructive sleep apnea syndrome (OSAS) is common in active acromegaly and negatively influences quality of life, morbidity, and mortality. This prospective study with 3 predetermined timepoints and a standardized treatment protocol investigates changes in sleep parameters during the first 2.5 years of acromegaly treatment. METHODS: Before initiation of acromegaly treatment (medical pretreatment followed by surgery), polysomnography (PSG) was performed in 27 consecutive patients with treatment-naive acromegaly. PSG was repeated after 1 year (N = 24) and 2.5 years (N = 23), and anthropometric and biochemical parameters were obtained. RESULTS: At baseline, 74.1% of the patients was diagnosed with OSAS. The respiratory disturbance index (RDI; P = 0.001), oxygen desaturation index (ODI; P = 0.001), lowest oxygen saturation (LSaO2; P = 0.007) and the Epworth Sleepiness Scale (ESS; P < 0.001) improved significantly during treatment, with the greatest improvement in the first year. After 2.5 years of treatment, all patients had controlled acromegaly. Of the 16 patients with repeated PSG and OSAS at baseline, 11 (68.8%) were cured of OSAS. Changes in RDI, ODI, LSaO2, and ESS correlated with insulin-like growth factor 1 levels. CONCLUSION: OSAS has a high prevalence in active acromegaly. There is a substantial decrease in prevalence and severity of OSAS following acromegaly treatment, with the largest improvement during the first year. Most patients recover from OSAS following surgical or biochemical control of the acromegaly. Therefore, a PSG is advised after diagnosis of acromegaly. When OSAS is present, it should be treated and PSG should be repeated during acromegaly treatment.


Assuntos
Acromegalia/complicações , Acromegalia/epidemiologia , Acromegalia/terapia , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/epidemiologia , Apneia Obstrutiva do Sono/patologia , Acromegalia/diagnóstico , Adenoma/complicações , Adenoma/epidemiologia , Adenoma/terapia , Adulto , Idoso , Estudos de Casos e Controles , Progressão da Doença , Agonistas de Dopamina/uso terapêutico , Feminino , Adenoma Hipofisário Secretor de Hormônio do Crescimento/complicações , Adenoma Hipofisário Secretor de Hormônio do Crescimento/epidemiologia , Adenoma Hipofisário Secretor de Hormônio do Crescimento/terapia , Hormônio do Crescimento Humano/análogos & derivados , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Procedimentos Neurocirúrgicos , Polissonografia , Prevalência , Prognóstico , Apneia Obstrutiva do Sono/diagnóstico , Sonolência , Resultado do Tratamento
8.
J Magn Reson Imaging ; 51(6): 1679-1688, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31799782

RESUMO

BACKGROUND: The glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide may be beneficial in the regression of diabetic cardiomyopathy. South Asian ethnic groups in particular are at risk of developing type 2 diabetes. PURPOSE: To assess the effects of liraglutide on left ventricular (LV) diastolic and systolic function in South Asian type 2 diabetes patients. STUDY TYPE: Prospective, double-blind, randomized, placebo-controlled trial. POPULATION: Forty-seven type 2 diabetes patients of South Asian ancestry living in the Netherlands, with or without ischemic heart disease, who were randomly assigned to 26-week treatment with liraglutide (1.8 mg/day) or placebo. FIELD STRENGTH/SEQUENCE: 3T (balanced steady-state free precession cine MRI, 2D and 4D velocity-encoded MRI, 1 H-MRS, T1 mapping). ASSESSMENT: Primary endpoints were changes in LV diastolic function (early deceleration peak [Edec], ratio of early and late peak filling rate [E/A], estimated LV filling pressure [E/Ea]) and LV systolic function (ejection fraction). Secondary endpoints were changes in aortic stiffness (aortic pulse wave velocity [PWV]), myocardial steatosis (myocardial triglyceride content), and diffuse fibrosis (extracellular volume [ECV]). STATISTICAL TESTS: Data were analyzed according to intention-to-treat. Between-group differences were reported as mean (95% confidence interval [CI]) and were assessed using analysis of covariance (ANCOVA). RESULTS: Liraglutide (n = 22) compared with placebo (n = 25) did not change Edec (+0.2 mL/s2 × 10-3 (-0.3;0.6)), E/A (-0.09 (-0.23;0.05)), E/Ea (+0.1 (-1.2;1.3)) and ejection fraction (0% (-3;2)), but decreased stroke volume (-9 mL (-14;-5)) and increased heart rate (+10 bpm (4;15)). Aortic PWV (+0.5 m/s (-0.6;1.6)), myocardial triglyceride content (+0.21% (-0.09;0.51)), and ECV (-0.2% (-1.4;1.0)) were unaltered. DATA CONCLUSION: Liraglutide did not affect LV diastolic and systolic function, aortic stiffness, myocardial triglyceride content, or extracellular volume in Dutch South Asian type 2 diabetes patients with or without coronary artery disease. LEVEL OF EVIDENCE: 1 Technical Efficacy Stage: 4 J. Magn. Reson. Imaging 2020;51:1679-1688.

9.
JAMA ; : 1-11, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31664429

RESUMO

Importance: It is unclear whether levothyroxine treatment provides clinically important benefits in adults aged 80 years and older with subclinical hypothyroidism. Objective: To determine the association of levothyroxine treatment for subclinical hypothyroidism with thyroid-related quality of life in adults aged 80 years and older. Design, Setting, and Participants: Prospectively planned combined analysis of data involving community-dwelling adults aged 80 years and older with subclinical hypothyroidism. Data from a randomized clinical trial were combined with a subgroup of participants aged 80 years and older from a second clinical trial. The trials were conducted between April 2013 and May 2018. Final follow-up was May 4, 2018. Exposures: Participants were randomly assigned to receive levothyroxine (n = 112; 52 participants from the first trial and 60 from the second trial) or placebo (n = 139; 53 participants from the first trial and 86 from the second trial). Main Outcomes and Measures: Co-primary outcomes were Thyroid-Related Quality of Life Patient-Reported Outcome (ThyPRO) questionnaire scores for the domains of hypothyroid symptoms and tiredness at 1 year (range, 0-100; higher scores indicate worse quality of life; minimal clinically important difference, 9). Results: Of 251 participants (mean age, 85 years; 118 [47%] women), 105 were included from the first clinical trial and 146 were included from the second clinical trial. A total of 212 participants (84%) completed the study. The hypothyroid symptoms score decreased from 21.7 at baseline to 19.3 at 12 months in the levothyroxine group vs from 19.8 at baseline to 17.4 at 12 months in the placebo group (adjusted between-group difference, 1.3 [95% CI, -2.7 to 5.2]; P = .53). The tiredness score increased from 25.5 at baseline to 28.2 at 12 months in the levothyroxine group vs from 25.1 at baseline to 28.7 at 12 months in the placebo group (adjusted between-group difference, -0.1 [95% CI, -4.5 to 4.3]; P = .96). At least 1 adverse event occurred in 33 participants (29.5%) in the levothyroxine group (the most common adverse event was cerebrovascular accident, which occurred in 3 participants [2.2%]) and 40 participants (28.8%) in the placebo group (the most common adverse event was pneumonia, which occurred in 4 [3.6%] participants). Conclusions and Relevance: In this prospectively planned analysis of data from 2 clinical trials involving adults aged 80 years and older with subclinical hypothyroidism, treatment with levothyroxine, compared with placebo, was not significantly associated with improvement in hypothyroid symptoms or fatigue. These findings do not support routine use of levothyroxine for treatment of subclinical hypothyroidism in adults aged 80 years and older. Trial Registration: ClinicalTrials.gov Identifier: NCT01660126; Netherlands Trial Register: NTR3851.

10.
Cardiovasc Diabetol ; 18(1): 133, 2019 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-31604432

RESUMO

BACKGROUND: The pathogenesis and cardiovascular impact of type 2 diabetes (T2D) may be different in South Asians compared with other ethnic groups. The phenotypic characterization of diabetic cardiomyopathy remains debated and little is known regarding differences in T2D-related cardiovascular remodeling across ethnicities. We aimed to characterize the differences in left ventricular (LV) diastolic and systolic function, LV structure, myocardial tissue characteristics and aortic stiffness between T2D patients and controls and to assess the differences in T2D-related cardiovascular remodeling between South Asians and Europeans. METHODS: T2D patients and controls of South Asian and European descent underwent 3 Tesla cardiovascular magnetic resonance imaging (CMR) and cardiac proton-magnetic resonance spectroscopy (1H-MRS). Differences in cardiovascular parameters between T2D patients and controls were examined using ANCOVA and were reported as mean (95% CI). Ethnic group comparisons in the association of T2D with cardiovascular remodeling were made by adding the interaction term between ethnicity and diabetes status to the model. RESULTS: A total of 131 individuals were included (54 South Asians [50.1 ± 8.7 years, 33% men, 33 patients vs. 21 controls) and 77 Europeans (58.8 ± 7.0 years, 56% men, 48 patients vs. 29 controls)]. The ratio of the transmitral early and late peak filling rate (E/A) was lower in T2D patients compared with controls, in South Asians [- 0.20 (- 0.36; - 0.03), P = 0.021] and Europeans [- 0.20 (- 0.36; - 0.04), P = 0.017], whereas global longitudinal strain and aortic pulse wave velocity were similar. South Asian T2D patients had a higher LV mass [+ 22 g (15; 30), P < 0.001] (P for interaction by ethnicity = 0.005) with a lower extracellular volume fraction [- 1.9% (- 3.4; - 0.4), P = 0.013] (P for interaction = 0.114), whilst European T2D patients had a higher myocardial triglyceride content [+ 0.59% (0.35; 0.84), P = 0.001] (P for interaction = 0.002) than their control group. CONCLUSIONS: Diabetic cardiomyopathy was characterized by impaired LV diastolic function in South Asians and Europeans. Increased LV mass was solely observed among South Asian T2D patients, whereas differences in myocardial triglyceride content between T2D patients and controls were only present in the European cohort. The diabetic cardiomyopathy phenotype may differ between subsets of T2D patients, for example across ethnicities, and tailored strategies for T2D management may be required.


Assuntos
Grupo com Ancestrais do Continente Asiático , Diabetes Mellitus Tipo 2/etnologia , Cardiomiopatias Diabéticas/etnologia , Grupo com Ancestrais do Continente Europeu , Disfunção Ventricular Esquerda/etnologia , Adulto , Idoso , Estudos de Casos e Controles , Estudos Transversais , Diabetes Mellitus Tipo 2/diagnóstico , Cardiomiopatias Diabéticas/diagnóstico por imagem , Cardiomiopatias Diabéticas/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Miocárdio/metabolismo , Miocárdio/patologia , Países Baixos/epidemiologia , Estudos Prospectivos , Triglicerídeos/metabolismo , Remodelação Vascular , Rigidez Vascular , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/fisiopatologia , Função Ventricular Esquerda , Remodelação Ventricular
11.
Sci Rep ; 9(1): 9996, 2019 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-31292457

RESUMO

Cholesteryl ester transfer protein (CETP) is mainly expressed by Kupffer cells in the liver. A reduction of hepatic triglyceride content (HTGC) by pioglitazone or caloric restriction is accompanied by a decrease in circulating CETP. Since GLP-1 analogues also reduce HTGC, we assessed whether liraglutide decreases CETP. Furthermore, we investigated the association between HTGC and CETP in a population-based cohort. In a placebo-controlled trial, 50 patients with type 2 diabetes were randomly assigned to treatment with liraglutide or placebo added to standard care. In this trial and in 1,611 participants of the Netherlands Epidemiology of Obesity (NEO) study, we measured HTGC and circulating CETP by proton magnetic resonance spectroscopy and ELISA, respectively. The HTGC was decreased in the liraglutide group (-6.3%; 95%CI of difference [-9.5, -3.0]) but also in the placebo group (-4.0%; 95%CI[-6.0, -2.0]), without between-group differences. CETP was not decreased by liraglutide (-0.05 µg/mL; 95%CI[-0.13, 0.04]) or placebo (-0.04 µg/mL; 95%CI[-0.12, 0.04]). No association was present between HTGC and CETP at baseline (ß: 0.002 µg/mL per %TG, 95%CI[-0.005, 0.009]) and between the changes after treatment with liraglutide (ß: 0.003 µg/mL per %TG, 95%CI[-0.010, 0.017]) or placebo (ß: 0.006 µg/mL per %TG, 95%CI[-0.012,0.024]). Also, in the cohort n o association between HTGC and CETP was present (ß: -0.001 µg/mL per SD TG, 95%CI[-0.005, 0.003]). A reduction of HTGC after treatment with liraglutide or placebo does not decrease circulating CETP. Also, no association between HTGC and CETP was present in a large cohort. These findings indicate that circulating CETP is not determined by HTGC.Clinical Trial Registration: Clinicaltrials.gov (NCT01761318).


Assuntos
Proteínas de Transferência de Ésteres de Colesterol/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Liraglutida/administração & dosagem , Fígado/química , Triglicerídeos/metabolismo , Adulto , Idoso , Diabetes Mellitus Tipo 2/metabolismo , Interação do Duplo Vínculo , Feminino , Humanos , Hipoglicemiantes/farmacologia , Liraglutida/farmacologia , Fígado/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento , Adulto Jovem
12.
Cardiovasc Diabetol ; 18(1): 87, 2019 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-31288820

RESUMO

BACKGROUND: South Asians have a high risk to develop type 2 diabetes, which may be related to substantial ectopic fat deposition. Since glucagon-like peptide-1 analogues can reduce ectopic fat accumulation, the aim of the present study was to assess the effect of treatment with liraglutide for 26 weeks on ectopic fat deposition and HbA1c in South Asian patients with type 2 diabetes. METHODS: In a placebo-controlled trial, 47 South Asian patients with type 2 diabetes were randomly assigned to treatment with liraglutide (1.8 mg/day) or placebo added to standard care. At baseline and after 26 weeks of treatment we assessed abdominal subcutaneous, visceral, epicardial and paracardial adipose tissue volume using MRI. Furthermore, myocardial and hepatic triglyceride content were examined with proton magnetic resonance spectroscopy. RESULTS: In the intention-to-treat analysis, liraglutide decreased body weight compared to placebo (- 3.9 ± 3.6 kg vs - 0.6 ± 2.2 kg; mean change from baseline (liraglutide vs placebo): - 3.5 kg; 95% CI [- 5.3, - 1.8]) without significant effects on the different adipose tissue compartments. HbA1c was decreased in both groups without between group differences. In the per-protocol analysis, liraglutide did decrease visceral adipose tissue volume compared to placebo (- 23 ± 27 cm2 vs - 2 ± 17 cm2; mean change from baseline (liraglutide vs placebo): - 17 cm2; 95% CI [- 32, - 3]). Furthermore, HbA1c was decreased by liraglutide compared to placebo (- 1.0 ± 0.8% (- 10.5 ± 9.1 mmol/mol)) vs (- 0.6 ± 0.8% (- 6.1 ± 8.8 mmol/mol)), with a between group difference (mean change from baseline (liraglutide vs placebo): - 0.6% (- 6.5 mmol/mol); 95% CI [- 1.1, - 0.1 (- 11.5, - 1.5)]). Interestingly, the decrease of visceral adipose tissue volume was associated with the reduction of HbA1c (ß: 0.165 mmol/mol (0.015%) per 1 cm2 decrease of visceral adipose tissue volume; 95% CI [0.062, 0.267 (0.006, 0.024%)]). CONCLUSIONS: While the intention-to-treat analysis did not show effects of liraglutide on ectopic fat and HbA1c, per-protocol analysis showed that liraglutide decreases visceral adipose tissue volume, which was associated with improved glycaemic control in South Asians. Trial registration NCT02660047 (clinicaltrials.gov). Registered 21 January 2016.


Assuntos
Adiposidade/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Incretinas/uso terapêutico , Gordura Intra-Abdominal/efeitos dos fármacos , Liraglutida/uso terapêutico , Adiposidade/etnologia , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etnologia , Diabetes Mellitus Tipo 2/fisiopatologia , Método Duplo-Cego , Feminino , Hemoglobina A Glicada/metabolismo , Humanos , Hipoglicemiantes/efeitos adversos , Incretinas/efeitos adversos , Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/fisiopatologia , Liraglutida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Fatores de Tempo , Resultado do Tratamento
13.
Cell Oncol (Dordr) ; 42(5): 691-703, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31201646

RESUMO

PURPOSE: Interleukin 32 (IL-32) is a pro-inflammatory cytokine of which different isoforms have been identified. Recently, IL-32 has been shown to act as a potent inducer of cell migration in several types of cancer. Although previous research showed that IL-32 is expressed in differentiated thyroid cancer (TC) cells, the role of IL-32 in TC cell migration has not been investigated. Furthermore, tumour-associated macrophages (TAMs) may play a facilitating role in cancer cell migration. The aim of this study was to explore whether the interaction between TC cells and TAMs results in increased expression of IL-32 in TC cells and to investigate whether this affects TC cell migration. METHODS: TPC-1 cells were co-culture with TC-induced or naive macrophages. Next, transcriptome analysis on TPC-1 cells was performed and supernatants were used for stimulation of TPC-1 cells. IL-32ß and IL-32γ were exogenously overexpressed in TPC-1 cells using transient transfection, after which an in vitro gap closure assay was performed to assess cell migration, and the expression of migratory factors was assessed using RT-qPCR. RESULTS: We found that TC-induced macrophages induced IL-32 expression in TC cells and that TAM-derived TNFα was the main inducer of IL-32ß expression in TC cells. Overexpression of IL-32ß and IL-32γ did not affect TC cell migration, but increased cell death. Finally, we found that IL-32ß overexpression led to increased mRNA expression of the pro-survival cytokine IL-8, while the expression of other migratory factors was not affected. CONCLUSIONS: From our data, we conclude that TAM-derived TNFα induces IL-32ß in TC cells. Although IL-32ß does not affect TC cell migration, alternative splicing of IL-32 towards the IL-32ß isoform may be beneficial for TC cell survival through induction of the pro-survival cytokine IL-8.


Assuntos
Movimento Celular/imunologia , Interleucinas/metabolismo , Macrófagos/imunologia , Neoplasias da Glândula Tireoide/imunologia , Fator de Necrose Tumoral alfa/farmacologia , Processamento Alternativo/genética , Morte Celular/efeitos dos fármacos , Morte Celular/imunologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Humanos , Interleucina-8/metabolismo , Interleucinas/genética , Antígeno Ki-67/imunologia , Monócitos/metabolismo , Isoformas de Proteínas/genética , Neoplasias da Glândula Tireoide/genética , Transcriptoma/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
14.
Sci Rep ; 9(1): 5396, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30932012

RESUMO

Sufficient thyroid iodine uptake is needed to ensure effective radioactive iodine (RAI) treatment, which is mediated by the sodium-iodide symporter (NIS). Activation of AMP-activated-protein-kinase (AMPK), leads to decreased NIS expression and thyroid iodine uptake in in vitro and animal models. Clinically relevant conditions that lead to AMPK activation include metformin use and hypocaloric conditions. Here, we aim to assess the effects of metformin and hypocaloric diet on thyroid iodine uptake in healthy volunteers. Healthy male volunteers were included and randomized. Group 1 (n = 8) received metformin, group 2 (n = 7) followed a hypocaloric diet (1500 kcal/day), superposed on a moderate iodine restriction diet; Baseline measurements included thyroid iodine-123 (I-123) uptake and TSH, fT4, T3 and rT3 levels. After two weeks, thyroid function and I-123 uptake measurements were repeated. Baseline characteristics were similar between groups. Levels of TSH and fT4 were similar after each intervention. T3 decreased after hypocaloric diet and metformin (-0.2 ± 0.19 nmol/L, p = 0.0327; respectively -0.13 ± 0.13 nmol/L, p = 0.0282), resulting in decreased T3/rT3 ratios. There was no significant difference in thyroid I-123 uptake after each intervention. In conclusion, metformin treatment and hypocaloric diet resulted in a significant decrease in T3 levels and T3/rT3 ratios in healthy volunteers, without significant effects on thyroid iodine uptake. We found no indications that metformin or hypocaloric diet will have clinically relevant effects on RAI uptake.


Assuntos
Dieta Redutora/métodos , Metabolismo Energético/efeitos dos fármacos , Voluntários Saudáveis/estatística & dados numéricos , Metformina/farmacologia , Glândula Tireoide/efeitos dos fármacos , Glândula Tireoide/metabolismo , Adulto , Transporte Biológico/efeitos dos fármacos , Humanos , Hipoglicemiantes/farmacologia , Radioisótopos do Iodo/farmacocinética , Radioisótopos do Iodo/urina , Masculino , Tireotropina/sangue , Tiroxina/sangue , Tri-Iodotironina/sangue , Adulto Jovem
15.
Thyroid ; 29(4): 461-470, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30900516

RESUMO

BACKGROUND: Publication of the 2015 American Thyroid Association (ATA) management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer was met with disagreement by the extended nuclear medicine community with regard to some of the recommendations related to the diagnostic and therapeutic use of radioiodine (131I). Because of these concerns, the European Association of Nuclear Medicine and the Society of Nuclear Medicine and Molecular Imaging declined to endorse the ATA guidelines. As a result of these differences in opinion, patients and clinicians risk receiving conflicting advice with regard to several key thyroid cancer management issues. SUMMARY: To address some of the differences in opinion and controversies associated with the therapeutic uses of 131I in differentiated thyroid cancer constructively, the ATA, the European Association of Nuclear Medicine, the Society of Nuclear Medicine and Molecular Imaging, and the European Thyroid Association each sent senior leadership and subject-matter experts to a two-day interactive meeting. The goals of this first meeting were to (i) formalize the dialogue and activities between the four societies; (ii) discuss indications for 131I adjuvant treatment; (iii) define the optimal prescribed activity of 131I for adjuvant treatment; and (iv) clarify the definition and classification of 131I-refractory thyroid cancer. CONCLUSION: By fostering an open, productive, and evidence-based discussion, the Martinique meeting restored trust, confidence, and a sense of collegiality between individuals and organizations that are committed to optimal thyroid disease management. The result of this first meeting is a set of nine principles (The Martinique Principles) that (i) describe a commitment to proactive, purposeful, and inclusive interdisciplinary cooperation; (ii) define the goals of 131I therapy as remnant ablation, adjuvant treatment, or treatment of known disease; (iii) describe the importance of evaluating postoperative disease status and multiple other factors beyond clinicopathologic staging in 131I therapy decision making; (iv) recognize that the optimal administered activity of 131I adjuvant treatment cannot be definitely determined from the published literature; and (v) acknowledge that current definitions of 131I-refractory disease are suboptimal and do not represent definitive criteria to mandate whether 131I therapy should be recommended.


Assuntos
Diferenciação Celular , Radioisótopos do Iodo/uso terapêutico , Radioterapia (Especialidade)/normas , Compostos Radiofarmacêuticos/uso terapêutico , Neoplasias da Glândula Tireoide/radioterapia , Consenso , Medicina Baseada em Evidências/normas , Humanos , Radioisótopos do Iodo/efeitos adversos , Compostos Radiofarmacêuticos/efeitos adversos , Neoplasias da Glândula Tireoide/patologia
16.
Oncogene ; 38(19): 3743-3755, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30670777

RESUMO

PTEN hamartoma tumor syndrome (PHTS) is caused by inactivating germline PTEN mutations with subsequent activation of Akt-mTOR signaling, leading to an increased risk of developing thyroid carcinoma (TC). Activation of Akt-mTOR signaling is essential for innate immune cell activation and reprogramming of TC-induced macrophages. Here, we aim to assess the effect of PTEN mutations on innate immune cell function in PHTS patients, especially in the context of TC, using a unique ex vivo model. Monocyte-derived cytokine responses were assessed in 29 PHTS patients and 29 controls. To assess the functional profile of TC-induced-macrophages, a co-culture model with two TC cell lines was performed. Rapamycin, a lactate transport blocker and metformin were used as modulators of the Akt-mTOR pathway and cell metabolism. Monocytes from PHTS patients showed increased production of IL-6, TNF-α, IL-8 and MCP-1, and higher lactate production. After co-culture with TC cell lines, TC-induced macrophages showed significantly increased production of cytokines in both patients and controls, especially after co-culture with a PTEN-deficient TC cell line; these effects were abolished after use of rapamycin or a lactate transport blocker. Metformin blocked the production of anti-inflammatory cytokines. In conclusion, innate immune cells from PHTS patients have increased lactate production and a more proinflammatory phenotype, especially after co-culture with PTEN-deficient TC. Metformin promotes a proinflammatory phenotype by blocking anti-inflammatory cytokine response, whereas rapamycin reduces production of proinflammatory cytokines. This indicates that PHTS patients may benefit from treatment with mTOR blocking agents to limit the inflammatory response in the tumor microenvironment.


Assuntos
Mutação em Linhagem Germinativa , Síndrome do Hamartoma Múltiplo/imunologia , Imunidade Inata/genética , PTEN Fosfo-Hidrolase/genética , Adulto , Estudos de Casos e Controles , Linhagem Celular Tumoral , Técnicas de Cocultura , Citocinas/metabolismo , Síndrome do Hamartoma Múltiplo/genética , Humanos , Metformina/farmacologia , Pessoa de Meia-Idade , Monócitos/imunologia , PTEN Fosfo-Hidrolase/imunologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Neoplasias da Glândula Tireoide/patologia , beta-Glucanas/farmacologia
17.
J Infect Dis ; 219(9): 1474-1482, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30452713

RESUMO

BACKGROUND: Eosinophils are a prominent cell type in the host response to helminths, and some evidence suggests that neutrophils might also play a role. However, little is known about the activation status of these granulocytes during helminth infection. METHODS: We analyzed the expression of eosinophil and neutrophil activation markers in peripheral blood by flow cytometry and measured serum levels of eosinophil granule proteins in 300 subjects residing in an area endemic for soil-transmitted helminths (STH). The data generated are on samples before and after 1 year of 3-monthly albendazole treatment. RESULTS: Anthelmintic treatment significantly reduced the prevalence of STH. While eosinophil numbers were significantly higher in STH-infected compared to uninfected subjects and significantly decreased following albendazole treatment, there was no effect exerted by the helminths on either eosinophil nor neutrophil activation. Although at baseline eosinophil granule protein levels were not different between STH-infected and uninfected subjects, treatment significantly reduced the levels of eosinophil-derived neurotoxin (EDN) in those infected at baseline. CONCLUSIONS: These results show that besides decreasing eosinophil numbers, anthelmintic treatment does not significantly change the activation status of eosinophils, nor of neutrophils, and the only effect seen was a reduction in circulating levels of EDN. CLINICAL TRIALS REGISTRATION: http://www.isrctn.com/ISRCTN75636394.


Assuntos
Albendazol/uso terapêutico , Anti-Helmínticos/uso terapêutico , Proteínas Granulares de Eosinófilos/sangue , Eosinófilos/metabolismo , Helmintíase/sangue , Adulto , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Grupo com Ancestrais do Continente Asiático , Biomarcadores/sangue , Antígeno CD11b/metabolismo , Estudos de Casos e Controles , Moléculas de Adesão Celular/metabolismo , Proteína Catiônica de Eosinófilo/sangue , Proteína Básica Maior de Eosinófilos/sangue , Neurotoxina Derivada de Eosinófilo/sangue , Eosinófilos/imunologia , Grupo com Ancestrais do Continente Europeu , Feminino , Proteínas Ligadas por GPI/metabolismo , Helmintíase/tratamento farmacológico , Helmintíase/imunologia , Humanos , Indonésia , Selectina L/metabolismo , Lectinas Tipo C/metabolismo , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Ativação de Neutrófilo , Neutrófilos/imunologia , Neutrófilos/metabolismo , Receptores de Complemento 3b/metabolismo
18.
Endocrine ; 62(1): 136-143, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29959689

RESUMO

OBJECTIVE: Intrinsic imperfections of thyroid hormone replacement therapy may affect long-term general well-being. In patients with Hashimoto thyroiditis (HT), cognitive functioning may be affected via altered thyroid hormones action as well as by the autoimmune process. The aim of this study was to evaluate cognitive function and quality of life (QoL) in patients on long-term levothyroxine replacement for HT in relation to thyroid function tests and TPO (thyroid-peroxidase) antibody (TPOAb) status. DESIGN: Retrospective cross-sectional study. PATIENTS AND MEASUREMENTS: One-hundred-and thirty patients with HT on long-term levothyroxine replacement and 111 euthyroid control subjects. Both groups were divided into two age subgroups, 20-49 years (N = 59 vs N = 79) and > 50 years (N = 71 vs N = 32). Evaluation included biochemical and neuropsychological tests, evaluating attention, global cognitive status, verbal and working memory, executive function, depression and anxiety, and quality of life. We used ANOVA and partial correlations to test for significant associations. RESULTS: FT4 (free-thyroxine), FT3 (free-triiodothyronine) levels and FT3/FT4 ratio were not different between patients and controls. Mean TSH (thyroid-stimulating hormone) was normal in all subjects but significantly higher in the patients (20-49 yrs:3.64 ± 2.74 vs 1.93 ± 1.10, >50 yrs:3.93 ± 2.84 vs 1.91 ± 0.90). Antibodies (TgAb,TPOAb) were higher in patients. Global cognitive function (MMSE-Mini mental state examination), conceptual tracking (TMT-Trail Making Test:A/B), verbal divergent thinking (like Phonemic fluency test), and anxiety and depression scores were significantly worse in patients vs controls. QoL was impaired in patients. there was a significant negative correlation between antibodies (TPOAb, TgAb) and quality in life (total SF36 score). CONCLUSION: Patients on long-term levothyroxine replacement show persistent impairments in both cognitive functioning and general well-being.


Assuntos
Cognição/fisiologia , Doença de Hashimoto/psicologia , Terapia de Reposição Hormonal/psicologia , Qualidade de Vida/psicologia , Tiroxina/uso terapêutico , Adulto , Atenção/fisiologia , Estudos Transversais , Função Executiva/fisiologia , Feminino , Doença de Hashimoto/tratamento farmacológico , Humanos , Masculino , Memória de Curto Prazo/fisiologia , Pessoa de Meia-Idade , Testes Neuropsicológicos , Estudos Retrospectivos , Adulto Jovem
19.
Sci Rep ; 8(1): 8149, 2018 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-29802315

RESUMO

Epidemiological studies have indicated that rural living might be protective against type 2 diabetes development. We compared the metabolic profile and response to a short-term high-fat high-calorie diet (HFD) of men with the same genetic background living in an urban and rural area of Indonesia. First, we recruited 154 Floresian male subjects (18-65 years old), of whom 105 lived in a rural area (Flores) and 49 had migrated and lived in urban area (Jakarta) for more than 1 year. The urban group had significantly higher whole-body insulin resistance (IR), as assessed by homeostatic-model-assessment of IR (HOMA-IR), [mean difference (95% CI), p-value: 0.10 (0.02-0.17), p = 0.01]. Next, we recruited 17 urban and 17 rural age-and-BMI-matched healthy-young-male volunteers for a 5-day HFD challenge. The HOMA-IR increased in both groups similarly -0.77 (-2.03-0.49), p = 0.22]. Neither rural living nor factors associated with rural living, such as current helminth infection or total IgE, were associated with protection against acute induction of IR by HFD.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Metabolômica , População Rural/estatística & dados numéricos , População Urbana/estatística & dados numéricos , Adolescente , Adulto , Idoso , Humanos , Resistência à Insulina , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Adulto Jovem
20.
Nutr Diabetes ; 8(1): 6, 2018 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-29343706

RESUMO

BACKGROUND/OBJECTIVES: Endocannabinoids (ECs) are associated with obesity and ectopic fat accumulation, both of which play a role in the development of cardiovascular disease (CVD) in type 2 diabetes (T2D). The effect of prolonged caloric restriction on ECs in relation to fat distribution and cardiac function is still unknown. Therefore, our aim was to investigate this relationship in obese T2D patients with coronary artery disease (CAD). SUBJECTS/METHODS: In a prospective intervention study, obese T2D patients with CAD (n = 27) followed a 16 week very low calorie diet (VLCD; 450-1000 kcal/day). Cardiac function and fat accumulation were assessed with MRI and spectroscopy. Plasma levels of lipid species, including ECs, were measured using liquid chromatography-mass spectrometry. RESULTS: VLCD decreased plasma levels of virtually all measured lipid species of the class of N-acylethanolamines including the EC anandamide (AEA; -15%, p = 0.016), without decreasing monoacylglycerols including the EC 2-arachidonoylglycerol (2-AG). Baseline plasma AEA levels strongly correlated with the volume of subcutaneous white adipose tissue (SAT; R2 = 0.44, p < 0.001). VLCD decreased the volume of SAT (-53%, p < 0.001), visceral white adipose tissue (VAT) (-52%, p < 0.001), epicardial white adipose tissue (-15%, p < 0.001) and paracardial white adipose tissue (-28%, p < 0.001). VLCD also decreased hepatic (-86%, p < 0.001) and myocardial (-33%, p < 0.001) fat content. These effects were accompanied by an increased left ventricular ejection fraction (54.8 ± 8.7-56.2 ± 7.9%, p = 0.016). CONCLUSIONS: Caloric restriction in T2D patients with CAD decreases AEA levels, but not 2-AG levels, which is paralleled by decreased lipid accumulation in adipose tissue, liver and heart, and improved cardiovascular function. Interestingly, baseline AEA levels strongly correlated with SAT volume. We anticipate that dietary interventions are worthwhile strategies in advanced T2D, and that reduction in AEA may contribute to the improved cardiometabolic phenotype induced by weight loss.


Assuntos
Tecido Adiposo/metabolismo , Restrição Calórica , Doença da Artéria Coronariana/dietoterapia , Diabetes Mellitus Tipo 2/dietoterapia , Dieta Redutora , Endocanabinoides/sangue , Função Ventricular Esquerda , Idoso , Ácidos Araquidônicos/sangue , Distribuição da Gordura Corporal , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/fisiopatologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Ingestão de Energia , Etanolaminas/sangue , Feminino , Glicerídeos/sangue , Coração/fisiopatologia , Humanos , Metabolismo dos Lipídeos , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Miocárdio/metabolismo , Obesidade/sangue , Obesidade/complicações , Obesidade/dietoterapia , Obesidade/metabolismo , Alcamidas Poli-Insaturadas/sangue , Estudos Prospectivos , Perda de Peso/fisiologia
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