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1.
Mol Cell Endocrinol ; 426: 101-12, 2016 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-26911933

RESUMO

The transmembrane glycoprotein CD26 or dipeptidyl peptidase IV (DPPIV) is a multifunctional protein. In immune system, CD26 plays a role in T-cell function and is also involved in thymic maturation and emigration patterns. In preclinical studies, treatment with DPPIV inhibitors reduces insulitis and delays or even reverses the new -onset of type 1 diabetes (T1D) in non-obese diabetic (NOD) mice. However, the specific mechanisms involved in these effects remain unknown. The aim of the present study was to investigate how DPPIV inhibition modifies the expression of genes in the thymus of NOD mice by microarray analysis. Changes in the gene expression of ß-cell autoantigens and Aire in thymic epithelial cells (TECs) were also evaluated by using qRT-PCR. A DPPIV inhibitor, MK626, was orally administered in the diet for 4 and 6 weeks starting at 6-8 weeks of age. Thymic glands from treated and control mice were obtained for each study checkpoint. Thymus transcriptome analysis revealed that 58 genes were significantly over-expressed in MK626-treated mice after 6 weeks of treatment. Changes in gene expression in the thymus were confined mainly to the immune system, including innate immunity, chemotaxis, antigen presentation and immunoregulation. Most of the genes are implicated in central tolerance mechanisms through several pathways. No differences were observed in the expression of Aire and ß-cell autoantigens in TECs. In the current study, we demonstrate that treatment with the DPPIV inhibitor MK626 in NOD mice alters the expression of the immune response-related genes in the thymus, especially those related to immunological central tolerance, and may contribute to the prevention of T1D.


Assuntos
Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Indinavir/farmacologia , Animais , Apresentação do Antígeno/genética , Feminino , Regulação da Expressão Gênica/imunologia , Redes Reguladoras de Genes , Imunomodulação/genética , Camundongos Endogâmicos NOD , Timo/efeitos dos fármacos , Timo/metabolismo , Transcriptoma
2.
PLoS One ; 10(11): e0142186, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26555789

RESUMO

CD26 is a T cell activation marker consisting in a type II transmembrane glycoprotein with dipeptidyl peptidase IV (DPPIV) activity in its extracellular domain. It has been described that DPPIV inhibition delays the onset of type 1 diabetes and reverses the disease in non-obese diabetic (NOD) mice. The aim of the present study was to assess the effect of MK626, a DPPIV inhibitor, in type 1 diabetes incidence and in T lymphocyte subsets at central and peripheral compartments. Pre-diabetic NOD mice were treated with MK626. Diabetes incidence, insulitis score, and phenotyping of T lymphocytes in the thymus, spleen and pancreatic lymph nodes were determined after 4 and 6 weeks of treatment, as well as alterations in the expression of genes encoding ß-cell autoantigens in the islets. The effect of MK626 was also assessed in two in vitro assays to determine proliferative and immunosuppressive effects. Results show that MK626 treatment reduces type 1 diabetes incidence and after 6 weeks of treatment reduces insulitis. No differences were observed in the percentage of T lymphocyte subsets from central and peripheral compartments between treated and control mice. MK626 increased the expression of CD26 in CD8+ T effector memory (TEM) from spleen and pancreatic lymph nodes and in CD8+ T cells from islet infiltration. CD8+TEM cells showed an increased proliferation rate and cytokine secretion in the presence of MK626. Moreover, the combination of CD8+ TEM cells and MK626 induces an immunosuppressive response. In conclusion, treatment with the DPPIV inhibitor MK626 prevents experimental type 1 diabetes in association to increase expression of CD26 in the CD8+ TEM lymphocyte subset. In vitro assays suggest an immunoregulatory role of CD8+ TEM cells that may be involved in the protection against autoimmunity to ß pancreatic islets associated to DPPIV inhibitor treatment.


Assuntos
Linfócitos T CD8-Positivos/efeitos dos fármacos , Diabetes Mellitus Tipo 1/prevenção & controle , Dipeptidil Peptidase 4/efeitos dos fármacos , Inibidores da Dipeptidil Peptidase IV/farmacologia , Fosfato de Sitagliptina/análogos & derivados , Animais , Autoantígenos/genética , Linfócitos T CD8-Positivos/imunologia , Diabetes Mellitus Tipo 1/imunologia , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/imunologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos NOD , Fosfato de Sitagliptina/farmacologia , Fator de Crescimento Transformador beta/sangue
3.
World J Diabetes ; 6(2): 321-5, 2015 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-25789113

RESUMO

Hepatic glycogenosis (HG) is characterized by excessive glycogen accumulation in hepatocytes and represents a hepatic complication of diabetes that particularly occurs in patients with longstanding poorly controlled type 1 diabetes (T1D). HG has been reported to be a very rare disease, although it is believed to be extremely underdiagnosed because it is not possible to distinguish it from non-alcoholic fatty liver disease (NAFLD) unless a liver biopsy is performed. In contrast to HG, NAFLD is characterized by liver fat accumulation and is the more likely diagnosis for patients with type 2 diabetes and metabolic syndrome. The pathogenesis of HG involves the concomitant presence of insulin and excess glucose, which increases glycogen storage in the liver. HG is characterized by a transient elevation in liver transaminases and hepatomegaly. Differentiating between these two conditions is of the utmost importance because HG is a benign disease that is potentially reversible by improving glycemic control, whereas NAFLD can progress to cirrhosis. Therefore, HG should be suspected when liver dysfunction occurs in patients with poorly controlled T1D. The aim of this article is to review the epidemiology, clinical characteristics, pathogenesis and histology of HG.

4.
Am J Surg ; 206(5): 783-9, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23835208

RESUMO

BACKGROUND: There is no consensus about the usefulness of postoperative intact parathyroid hormone (iPTH) determination to predict permanent hypoparathyroidism (pHPP). We evaluated the value of calcium (Ca2+) and iPTH concentration at 24 hours after total thyroidectomy (TT) for predicting pHPP. METHODS: Ca2+ and iPTH levels from 70 consecutive patients who underwent TT were measured at 24 hours and 6 months after TT. RESULTS: Five patients (7.1%) developed pHPP. An iPTH concentration ≤5.8 pg/mL at 24 hours after TT identified patients at risk for pHPP (sensitivity, 100%; specificity, 81.5%), but it was not accurate enough to predict its development (positive predictive value, 30%). Conversely, an iPTH level >5.8 pg/mL predicted normal parathyroid function at 6 months (negative predictive value, 100%). Compared with iPTH, a postoperative Ca2+ level ≤1.95 mmol/L was 60% sensitive and 78.5% specific to predict pHPP. CONCLUSIONS: An iPTH concentration >5.8 pg/mL on the first postoperative day rules out pHPP with much better diagnostic accuracy than Ca2+. Postoperative iPTH could be helpful in identifying patients at risk for developing pHPP.


Assuntos
Cálcio/sangue , Hipoparatireoidismo/diagnóstico , Hormônio Paratireóideo/sangue , Tireoidectomia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Valor Preditivo dos Testes , Estudos Prospectivos , Curva ROC , Sensibilidade e Especificidade , Fatores de Tempo
5.
Thyroid ; 23(8): 964-70, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23528137

RESUMO

BACKGROUND: The relationship between thyrotropin (TSH) concentrations and body mass index (BMI) in euthyroid subjects has been demonstrated only in some studies. Leptin regulates TSH secretion and TSH stimulates leptin secretion. The main aims of our study were to assess the relationship between leptin, the thyroid axis, and thyroid autoimmunity in a representative sample of a nonhospitalized euthyroid adult population of Catalonia and to determine whether smoking status could influence this relationship. METHODS: This cross-sectional population-based study includes 894 euthyroid iodine-sufficient adults (390 men, 44.87±15.03 years old) with BMI 26.19±4.61 kg/m(2), representative of people living in Catalonia. The study analyzes the relationship between TSH, free thyroxine (FT4), leptin, thyroperoxidase and/or thyroglobulin antibodies (thyroid autoimmunity), smoking status, and BMI. Measurements also include glycemia and insulinemia to calculate homeostasis model assessment of insulin resistance (HOMA-IR) index as a measure of insulin sensitivity. RESULTS: In the univariate analysis and in the overall group, TSH correlated directly with BMI, leptin, and HOMA-IR (p=0.039, p<0.001, and p=0.010, respectively). In all men, TSH correlated directly with leptin (p=0.004), and in all women, directly with leptin (p=0.002) and HOMA-IR (p=0.031) and inversely with FT4 (p=0.024). Only in men who smoke, TSH correlated directly with leptin (p=0.010) and HOMA-IR (p=0.024). In women, TSH correlated directly with leptin (p=0.004) and in nonsmoking women, inversely with FT4 (p=0.047). In the multiple regression analysis, age (ß=-0.00310, p=0.0265), smoking status (ß=-0.24085, p=0.0202), and thyroid autoimmunity (ß=0.20652, p=0.0075) were independent predictors of TSH variations. Leptin was a significant independent predictor of TSH variations only in smokers (ß=0.16451, p=0.047). CONCLUSIONS: Leptin is an independent predictor of TSH concentration variations only in euthyroid smoker subjects of both sexes at all ranges of BMI, but not in nonsmokers. Age, smoking status, and positive thyroid autoimmunity also influenced TSH variability.


Assuntos
Leptina/sangue , Fumar/fisiopatologia , Glândula Tireoide/fisiologia , Tireotropina/sangue , Adolescente , Adulto , Idoso , Autoanticorpos/sangue , Glicemia/metabolismo , Índice de Massa Corporal , Estudos Transversais , Feminino , Homeostase , Humanos , Resistência à Insulina/fisiologia , Iodeto Peroxidase/sangue , Masculino , Pessoa de Meia-Idade , Glândula Tireoide/imunologia , Tiroxina/sangue
6.
Eur J Endocrinol ; 168(1): 9-13, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23038625

RESUMO

OBJECTIVE: Most cases of familial isolated pituitary adenomas with mutated aryl hydrocarbon receptor-interacting protein (AIP:HGNC:358) gene develop somatotropinomas. They are characterised by an aggressive clinical phenotype including early age at diagnosis, large tumours and frequent invasiveness. There is little information on AIP gene mutations' prevalence in isolated somatotropinomas characterised by poor response to somatostatin analogue treatment. The aim of this study was to investigate the prevalence of AIP mutations in non-familial cases of somatotropinomas with poor response to conventional treatment. DESIGN AND METHODS: Fifty patients with acromegaly (22 males/28 females, age 51±18 years) and 60 controls were included in this study performed at eight University Hospitals in Spain. None had family history of pituitary adenomas or other endocrine tumors. All patients failed to respond to conventional treatment including surgery and somatostatin analogues. Some patients received adjuvant radiotherapy and most cases required pegvisomant (PEG) treatment for normalisation of IGF1. AIP analysis was performed in DNA extracted from peripheral leucocytes, using standardised PCR protocol in which the coding regions of exons 1, 2, 3, 4, 5 and 6 were amplified. Possible deletions/duplications were studied using multiplex ligation-dependent probe amplification. RESULTS: SEQUENCE CHANGES OF POTENTIAL DIFFERENT SIGNIFICANCE THAT COULD BE CONSIDERED AS MUTATIONS OR VARIATIONS OF UNKNOWN SIGNIFICANCE (VUS) OF THE AIP GENE WERE FOUND IN FOUR PATIENTS (8%). IN TWO CASES, TWO DIFFERENT MUTATIONS PREVIOUSLY DESCRIBED WERE FOUND: p.Arg9Gln and p.Phe269Phe. Two other VUS were also found: c.787+24C>T in intron 5 and c.100-18C>T in intron 1. Age at diagnosis ranged from 21 to 50 years old, and in all patients, the tumor was a macroadenoma depicting IGF1 normalisation under PEG treatment. CONCLUSIONS: AIP germline mutations show a low, but non-negligible, prevalence in non-familial acromegaly patients with tumors resistant to treatment with somatostatin analogues.


Assuntos
Acromegalia/genética , Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Acromegalia/tratamento farmacológico , Adenoma/tratamento farmacológico , Adenoma/genética , Adulto , Idoso , Resistencia a Medicamentos Antineoplásicos , Feminino , Mutação em Linhagem Germinativa , Adenoma Hipofisário Secretor de Hormônio do Crescimento/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Multiplex , Somatostatina/análogos & derivados , Somatostatina/uso terapêutico
8.
Endocrine ; 38(3): 391-6, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20972723

RESUMO

The prevalence of thyroid dysfunction varies in different populations. The aim of this cross-sectional study was to analyze the prevalence of undiagnosed thyroid dysfunction and thyroid antibodies and their relationship with urine iodine excretion in a representative sample of 1,124 (55.5% women; mean age: 44.8 ± 15.2 years) non-hospitalized Mediterranean adults, in Catalonia (Spain). Free thyroxine, thyroid-stimulating hormone, thyroperoxidase and thyroglobulin antibodies, and urine iodine were measured. Undiagnosed thyroid dysfunction was 5.3% (hypothyroidism 3.8%; 56.66% of these subjects were women). The total (diagnosed + undiagnosed) thyroid dysfunction was 8.9% (71.15% women). Thyroperoxidase antibodies were positive in 2.4% of men and 9.4% of women and thyroglobulin antibodies, in 1.3% of men and 3.8% of women. No differences were observed in urine iodine between groups with thyroid dysfunction and euthyroidism, or between subjects with positive or negative antibodies. In subjects over 60, undiagnosed thyroid dysfunction was 9.8% (hypothyroidism 6.9%, hyperthyroidism 3.3%; 36.36% women) and total thyroid dysfunction 13.61% (53.12% women). Women and men over 60 had similar thyroid dysfunction prevalence. Thus, aggressive case-finding should be recommended in both, over 60.


Assuntos
Anticorpos/sangue , Iodo/urina , Doenças da Glândula Tireoide/epidemiologia , Glândula Tireoide/imunologia , Adulto , Doenças Assintomáticas/epidemiologia , Diagnóstico Tardio/estatística & dados numéricos , Feminino , Humanos , Iodo/metabolismo , Masculino , Região do Mediterrâneo/epidemiologia , Pessoa de Meia-Idade , População , Prevalência , Espanha/epidemiologia , Doenças da Glândula Tireoide/sangue , Doenças da Glândula Tireoide/diagnóstico , Doenças da Glândula Tireoide/urina , Testes de Função Tireóidea
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