Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 24
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
BMC Endocr Disord ; 23(1): 118, 2023 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-37231428

RESUMO

BACKGROUND: Heterozygous loss-of-function mutations in the chromodomain helicase DNA-binding protein 7 (CHD7) gene cause CHARGE syndrome characterized by various congenital anomalies. A majority of patients with CHARGE syndrome present with congenital hypogonadotropic hypogonadism (HH), and combined pituitary hormone deficiency (CPHD) can also be present. Whereas CHD7 mutations have been identified in some patients with isolated HH without a diagnosis of CHARGE syndrome, it remains unclear whether CHD7 mutations can be identified in patients with CPHD who do not fulfill the criteria for CHARGE syndrome. CASE PRESENTATION: A 33-year-old woman was admitted to our hospital. She had primary amenorrhea and was at Tanner stage 2 for both pubic hair and breast development. She was diagnosed with CPHD (HH, growth hormone deficiency, and central hypothyroidism), and a heterozygous rare missense mutation (c.6745G > A, p.Asp2249Asn) in the CHD7 gene was identified. Our conservation analysis and numerous in silico analyses suggested that this mutation had pathogenic potential. She had mild intellectual disability, a minor feature of CHARGE syndrome, but did not fulfill the criteria for CHARGE syndrome. CONCLUSIONS: We report a rare case of CPHD harboring CHD7 mutation without CHARGE syndrome. This case provides valuable insights into phenotypes caused by CHD7 mutations. CHD7 mutations can have a continuous phenotypic spectrum depending on the severity of hypopituitarism and CHARGE features. Therefore, we would like to propose a novel concept of CHD7-associated syndrome.


Assuntos
Síndrome CHARGE , Hipogonadismo , Hipopituitarismo , Feminino , Humanos , Síndrome CHARGE/diagnóstico , Síndrome CHARGE/genética , Mutação de Sentido Incorreto , Mutação , Hipopituitarismo/genética , Hipogonadismo/genética , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo
2.
Diabetol Int ; 14(2): 211-216, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37090132

RESUMO

Exogenous insulin can induce insulin antibodies that have a low affinity/high binding capacity. Similar to what is observed in insulin autoimmune syndrome, these insulin antibodies can cause fasting hypoglycemia and postprandial hyperglycemia, a phenomenon known as "exogenous insulin antibody syndrome" (EIAS). Cases of EIAS in patients with type 1 and type 2 diabetes have been sporadically reported, mainly in Asia. However, there has been no report on EIAS in patients with diabetes secondary to total pancreatectomy treated with insulin analogs. A 74-year-old man with diabetes after total pancreatectomy had been treated with continuous subcutaneous insulin infusion using an insulin analog, lispro, and developed recurrent early morning hypoglycemia even after discontinuation of nocturnal basal insulin. His fasting serum lispro level was high even approximately 9 h after the last lispro dose. He had a high titer (72.7%) of insulin antibodies, and a Scatchard analysis revealed low affinity/high binding capacity. These findings suggested that the patient's recurrent early morning hypoglycemia was associated with insulin antibodies against lispro, and we, therefore, switched from lispro to another insulin analog, glulisine. His hypoglycemia improved, accompanied by a dramatic decrease in his insulin antibodies and serum glulisine levels. Early morning hypoglycemia in patients with diabetes secondary to total pancreatectomy may often be explained by high glycemic variability, malnutrition, and/or glucagon deficiency. However, in cases of recurrent early morning hypoglycemia, EIAS should be considered as a potential differential diagnosis.

3.
Intern Med ; 61(15): 2333-2337, 2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35598993

RESUMO

Metformin-associated lactic acidosis (MALA) is an extremely rare but life-threatening adverse effect of metformin treatment. The lifestyle changes associated with the coronavirus disease 2019 (COVID-19) pandemic may increase the potential risk of MALA development in patients with diabetes. We herein report a 64-year-old Japanese man taking a small dose of metformin who presented with MALA accompanied by hypoglycemia secondary to increased alcohol consumption triggered by lifestyle changes during the pandemic. Physicians should prescribe metformin judiciously to prevent MALA development and pay close attention to lifestyle changes in patients at risk for MALA during the COVID-19 pandemic.


Assuntos
Acidose Láctica , COVID-19 , Diabetes Mellitus Tipo 2 , Hipoglicemia , Metformina , Acidose Láctica/induzido quimicamente , Diabetes Mellitus Tipo 2/complicações , Humanos , Hipoglicemia/tratamento farmacológico , Hipoglicemiantes/efeitos adversos , Masculino , Metformina/efeitos adversos , Pessoa de Meia-Idade , Pandemias
4.
J Endocr Soc ; 6(3): bvac009, 2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-35187382

RESUMO

Primary aldosteronism (PA) is a state of renin-independent aldosterone secretion that can range from subclinical to overt. Some normotensive individuals for whom PA screening is not routinely recommended are reported to fulfill the loading test criterion used for the diagnosis of PA. Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by the development of various endocrine tumors. Cases of PA associated with MEN1 have been reported; however, there has been no previous report on renin-independent aldosterone secretion within a family with MEN1. Herein, we present the case of a normotensive family presenting with both MEN1 and renin-independent aldosterone secretion. A 49-year-old man was admitted to our hospital for PA evaluation owing to the plasma aldosterone concentration/plasma renin activity ratio being greater than the screening cut-off value; the patient was normotensive. The patient had a history of left nephrectomy and adrenalectomy for left renal carcinoma and adrenal tumor at the age of 39 years. Subsequently, he was diagnosed with MEN1 concurrent with primary hyperparathyroidism, insulinoma, and novel MEN1 gene mutations (c.655-5_655-4insC and c.818delC). The loading tests for PA confirmation, including saline infusion, and furosemide upright and captopril challenge tests, yielded positive findings, confirming a case of renin-independent aldosterone secretion. The patient's mother, brother, and sister were also genetically or clinically diagnosed with MEN1. All of them were also normotensive and confirmed to have renin-independent aldosterone secretion. The coexistence of renin-independent aldosterone secretion and MEN1 within this family suggests a relationship between the 2 entities.

5.
J Diabetes Investig ; 13(2): 391-396, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34382350

RESUMO

2p25.3 deletion syndrome is a rare genetic disorder that accompanies various phenotypic features, including early-onset obesity and intellectual disability. Here, we report the first Japanese case of this deletion associated with severe obesity and diabetes mellitus. Microarray-based comparative genomic hybridization analysis identified a 3.1-Mb deletion of distal chromosome band 2p25.3, which was suspected as de novo. The patient also presented bilateral cataracts and adolescent-onset muscular weakness of the upper limbs, both of which were uncommon in previously reported cases. It is possible that these symptoms are also important clinical features suggestive of this syndrome.


Assuntos
Diabetes Mellitus , Deficiência Intelectual , Adolescente , Hibridização Genômica Comparativa , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/genética , Japão , Obesidade/complicações , Obesidade/genética , Fenótipo
6.
Intern Med ; 61(3): 303-311, 2022 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-34803093

RESUMO

Objective This study evaluated the lifestyle changes in patients with diabetes and their independent associations with glycemic and body weight control. In addition, the correlation between changes in mental health and lifestyles was evaluated. Methods This single-center cross-sectional study included 340 patients with diabetes who periodically visited our department. Changes in dietary habits, activities of daily living, and mental health before and during approximately six months after the onset of the coronavirus disease 2019 (COVID-19) pandemic were evaluated using a questionnaire, including the International Physical Activity Questionnaire-Short Form. Results Approximately 20%, 30%, and over 50% of patients had worsened dietary habits, decreased activities of daily living, and deteriorated mental health, respectively. A multiple regression analysis showed that irregular meal timing was significantly associated with change in HbA1c (ß=0.328, p=0.001), and decreased walking time was significantly associated with changes in body weight (ß=-0.245, p=0.025). The change in fear and anxiety was positively associated with changes in meal timing regularity (r=0.129, p=0.019) and carbohydrate consumption (r=0.127, p=0.021). Subsequently, the change in depressed mood was positively associated with changes in carbohydrate (r=0.142, p=0.010) and alcohol (r=0.161, p=0.037) consumption, and the change in psychological stress was positively associated with changes in carbohydrates (r=0.183, p=0.001) and snack (r=0.151, p=0.008) consumption as well as sedentary time (r=0.158, p=0.004). Conclusion The COVID-19 pandemic has had a considerable medium-term impact on the lifestyle and mental health of patients with diabetes. Lifestyle changes were associated with glycemic and body weight control, and mental health changes were associated with lifestyle changes. These findings may provide important information on diabetes care during the pandemic.


Assuntos
COVID-19 , Diabetes Mellitus , Atividades Cotidianas , Estudos Transversais , Humanos , Pandemias , SARS-CoV-2
7.
Diabetol Int ; 12(2): 234-240, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33786278

RESUMO

We encountered a 55-year-old Japanese man with advanced renal cell carcinoma and slowly progressive type 1 diabetes mellitus (SPT1DM), whose insulin secretory capacity was drastically reduced for a brief period after only one cycle of immune checkpoint inhibitor (ICI) treatment. The patient had been diagnosed with type 2 diabetes at the age of 53 years and was treated using oral hypoglycemic agents. However, 2 years later, he was diagnosed with SPT1DM and autoimmune thyroiditis, based on the presence of anti-glutamic acid decarboxylase antibodies (GADA) and thyroid autoantibodies, which was accompanied by advanced renal cell carcinoma. At that time, his insulin secretory capacity was preserved (CPR 2.36 ng/mL), and good glycemic control was maintained using only medical nutrition therapy (HbA1c 6.3%). He subsequently developed destructive thyroiditis approximately 2 weeks after the first cycle of ICI treatment using nivolumab (a programmed cell death-1 inhibitor) and ipilimumab (a cytotoxic T-lymphocyte-associated antigen-4 inhibitor) for advanced renal cell carcinoma. Three weeks later, his plasma glucose level markedly increased, and we detected absolute insulin deficiency and hypothyroidism. Human leukocyte antigen (HLA) analysis revealed haplotypes indicating susceptibility to type 1 diabetes mellitus (T1DM) or autoimmune thyroiditis (HLA genotype, DRB1-DQB1 *09:01-*03:03/*08:03-*06:01). He showed a good antitumor response and is currently receiving permanent insulin therapy and levothyroxine replacement with the ICI treatment. Based on this case and the available literature, patients with preexisting islet autoantibodies or SPT1DM/LADA, plus a genetic predisposition to T1DM, may have an extremely high risk of developing ICI-related T1DM for a brief period after starting ICI treatment.

8.
Intern Med ; 60(6): 905-910, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33716254

RESUMO

Hypoglycemia should be avoided when treating patients with diabetes. Repaglinide is an insulin secretagogue with a low hypoglycemic risk because of its rapid- and short-acting effects. However, its blood concentration has been reported to increase in combination with clopidogrel, an antiplatelet drug, and in patients with severe renal insufficiency. We herein report an elderly patient with type 2 diabetes mellitus and severe renal insufficiency who received repaglinide and hypoglycemia three days after starting clopidogrel. The concomitant use of repaglinide and clopidogrel can lead to hypoglycemia, especially in patients with severe renal insufficiency.


Assuntos
Diabetes Mellitus Tipo 2 , Hipoglicemia , Insuficiência Renal , Idoso , Glicemia , Carbamatos , Clopidogrel/efeitos adversos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemia/tratamento farmacológico , Hipoglicemiantes/efeitos adversos , Piperidinas , Insuficiência Renal/induzido quimicamente , Insuficiência Renal/complicações
9.
Mol Ther ; 28(10): 2203-2219, 2020 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-32652045

RESUMO

Mesenchymal stem/stromal cells (MSCs) are cultured adult stem cells that originally reside in virtually all tissues, and the gain of MSCs by transplantation has become the leading form of cell therapy in various diseases. However, there is limited knowledge on the alteration of its efficacy by factors in recipients. Here, we report that the cardioprotective properties of intravenously injected MSCs in a mouse model of pressure-overload heart failure largely depend on circulating adiponectin, an adipocyte-secreted factor. The injected MSCs exert their function through exosomes, extracellular vesicles of endosome origin. Adiponectin stimulated exosome biogenesis and secretion through binding to T-cadherin, a unique glycosylphosphatidylinositol-anchored cadherin, on MSCs. A pharmacological or adenovirus-mediated genetic increase in plasma adiponectin enhanced the therapeutic efficacy of MSCs. Our findings provide novel insights into the importance of adiponectin in mesenchymal-progenitor-mediated organ protections.


Assuntos
Adiponectina/genética , Exossomos/metabolismo , Insuficiência Cardíaca/terapia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , Adiponectina/sangue , Adiponectina/metabolismo , Animais , Caderinas/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Suscetibilidade a Doenças , Vesículas Extracelulares/metabolismo , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Camundongos
11.
Am J Physiol Heart Circ Physiol ; 318(2): H238-H251, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31774689

RESUMO

A disintegrin and metalloproteinase (ADAM)12 is considered to promote cardiac dysfunction based on the finding that a small-molecule ADAM12 inhibitor, KB-R7785, ameliorated cardiac function in a transverse aortic constriction (TAC) model by inhibiting the proteolytic activation of heparin-binding-EGF signaling. However, this compound has poor selectivity for ADAM12, and the role of ADAM12 in cardiac dysfunction has not yet been investigated using genetic loss-of-function mice. We revealed that ADAM12 knockout mice showed significantly more advanced cardiac hypertrophy and higher mortality rates than wild-type mice 4 wk after TAC surgery. An ADAM12 deficiency resulted in significantly more expanded cardiac fibrosis accompanied by increased collagen-related gene expression in failing hearts. The results of a genome-wide transcriptional analysis suggested a strongly enhanced focal adhesion- and fibrosis-related signaling pathway in ADAM12 knockout hearts. The loss of ADAM12 increased the abundance of the integrinß1 subunit and transforming growth factor (TGF)-ß receptor types I and III, and this was followed by the phosphorylation of focal adhesion kinase, Akt, mammalian target of rapamycin, ERK, and Smad2/3 in the heart, which resulted in cardiac dysfunction. The present results revealed that the loss of ADAM12 enhanced focal adhesion and canonical TGF-ß signaling by regulating the abundance of the integrinß1 and TGF-ß receptors.NEW & NOTEWORTHY In contrast to a long-believed cardio-damaging role of a disintegrin and metalloproteinase (ADAM)12, cardiac hypertrophy was more severe, cardiac function was lower, and mortality was higher in ADAM12 knockout mice than in wild-type mice after transverse aortic constriction surgery. The loss of ADAM12 enhanced focal adhesion- and fibrosis-related signaling pathways in the heart, which may compromise cardiac function. These results provide insights for the development of novel therapeutics that target ADAM12 to treat heart failure.


Assuntos
Proteína ADAM12/genética , Cardiomegalia/prevenção & controle , Desintegrinas/uso terapêutico , Insuficiência Cardíaca/prevenção & controle , Miocárdio/patologia , Proteína ADAM12/antagonistas & inibidores , Proteína ADAM12/efeitos dos fármacos , Animais , Pressão Sanguínea , Fibrose , Adesões Focais/efeitos dos fármacos , Integrina beta1/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Fatores de Crescimento Transformadores beta/efeitos dos fármacos , Receptores de Fatores de Crescimento Transformadores beta/genética , Transdução de Sinais/efeitos dos fármacos
12.
Sci Rep ; 9(1): 16, 2019 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-30626897

RESUMO

Skeletal muscle has remarkable regenerative potential and its decline with aging is suggested to be one of the important causes of loss of muscle mass and quality of life in elderly adults. Metabolic abnormalities such as obesity were linked with decline of muscle regeneration. On the other hand, plasma levels of adiponectin are decreased in such metabolic conditions. However, plasma levels of adiponectin have been shown to inversely correlate with muscle mass and strength in elderly people especially with chronic heart failure (CHF). Here we have addressed whether adiponectin has some impact on muscle regeneration after cardiotoxin-induced muscle injury in mice. Muscle regeneration was delayed by angiotensin II infusion, mimicking aging and CHF as reported. Adiponectin overexpression in vivo decreased necrotic region and increased regenerating myofibers. Such enhanced regeneration by excess adiponectin was also observed in adiponectin null mice, but not in T-cadherin null mice. Mechanistically, adiponectin accumulated on plasma membrane of myofibers both in mice and human, and intracellularly colocalized with endosomes positive for a multivesicular bodies/exosomes marker CD63 in regenerating myofibers. Purified high-molecular multimeric adiponectin similarly accumulated intracellularly and colocalized with CD63-positive endosomes and enhanced exosome secretion in differentiating C2C12 myotubes but not in undifferentiated myoblasts. Knockdown of T-cadherin in differentiating C2C12 myotubes attenuated both adiponectin-accumulation and adiponectin-mediated exosome production. Collectively, our studies have firstly demonstrated that adiponectin stimulates muscle regeneration through T-cadherin, where intracellular accumulation and exosome-mediated process of adiponectin may have some roles.


Assuntos
Adiponectina/fisiologia , Caderinas/metabolismo , Músculo Esquelético , Regeneração , Envelhecimento/metabolismo , Animais , Linhagem Celular , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/fisiologia , Músculo Esquelético/fisiopatologia
13.
Am J Physiol Endocrinol Metab ; 316(2): E239-E250, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30457913

RESUMO

Glycosylphosphatidylinositol-specific phospholipase D (GPI-PLD) is an enzyme that specifically cleaves GPI anchors. Previous human studies suggested the relationship of GPI-PLD to insulin resistance, type 1 and type 2 diabetes, and nonalcoholic fatty liver disease (NAFLD). However, the biological roles of GPI-PLD have not been elucidated. Here, we hypothesized that GPI-PLD impacted on lipid and glucose metabolism, especially in the liver. GPI-PLD mRNA was most highly expressed in the liver, and the hepatic mRNA level and circulating concentration of GPI-PLD were significantly augmented in diabetic mice. To investigate in vivo functions of GPI-PLD, we generated GPI-PLD knockout (GP-KO) mice. Mice lacking GPI-PLD exhibited the amelioration of glucose intolerance and hepatic steatosis under high-fat and high-sucrose diet. Furthermore, diacylglycerol (DAG) content was significantly decreased, and PKCε activity was suppressed in the livers of GP-KO mice. In vitro knockdown and overexpression experiments of GPI-PLD using rat primary hepatocytes showed the GPI-PLD-dependent regulation of intracellular DAG content. Finally, serum GPI-PLD levels were strongly and independently associated with serum alanine transaminase (R = 0.37, P = 0.0006) and triglyceride (R = 0.34, P = 0.001) levels in male subjects with metabolic syndrome. In conclusion, upregulation of hepatic GPI-PLD in diabetic conditions leads to DAG accumulation in the liver by shedding GPI anchors intracellularly, which may play a causal role in impaired hepatic insulin signaling and the progression of NAFLD.


Assuntos
Diglicerídeos/metabolismo , Intolerância à Glucose/genética , Resistência à Insulina/genética , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , Obesidade/metabolismo , Fosfolipase D/genética , Idoso , Alanina Transaminase/metabolismo , Animais , Dieta Hiperlipídica , Sacarose Alimentar , Técnicas de Silenciamento de Genes , Glucose/metabolismo , Intolerância à Glucose/metabolismo , Hepatócitos/metabolismo , Humanos , Metabolismo dos Lipídeos/genética , Masculino , Síndrome Metabólica/metabolismo , Camundongos Knockout , Camundongos Obesos , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/metabolismo , Proteína Quinase C-épsilon/metabolismo , RNA Mensageiro/metabolismo , Ratos , Triglicerídeos/metabolismo
14.
JCI Insight ; 3(8)2018 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-29669945

RESUMO

Adiponectin, an adipocyte-derived circulating protein, accumulates in vasculature, heart, and skeletal muscles through interaction with a unique glycosylphosphatidylinositol-anchored cadherin, T-cadherin. Recent studies have demonstrated that such accumulation is essential for adiponectin-mediated cardiovascular protection. Here, we demonstrate that the adiponectin/T-cadherin system enhances exosome biogenesis and secretion, leading to the decrease of cellular ceramides. Adiponectin accumulated inside multivesicular bodies, the site of exosome generation, in cultured cells and in vivo aorta, and also in exosomes in conditioned media and in blood, together with T-cadherin. The systemic level of exosomes in blood was significantly affected by adiponectin or T-cadherin in vivo. Adiponectin increased exosome biogenesis from the cells, dependently on T-cadherin, but not on AdipoR1 or AdipoR2. Such enhancement of exosome release accompanied the reduction of cellular ceramides through ceramide efflux in exosomes. Consistently, the ceramide reduction by adiponectin was found in aortas of WT mice treated with angiotensin II, but not in T-cadherin-knockout mice. Our findings provide insights into adiponectin/T-cadherin-mediated organ protection through exosome biogenesis and secretion.


Assuntos
Adiponectina/metabolismo , Caderinas/metabolismo , Ceramidas/metabolismo , Exossomos/metabolismo , Adipócitos/metabolismo , Angiotensina II/administração & dosagem , Animais , Aorta/metabolismo , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/prevenção & controle , Células Cultivadas/metabolismo , Células Endoteliais/metabolismo , Masculino , Camundongos , Camundongos Knockout , Biogênese de Organelas
15.
Circ J ; 82(2): 502-508, 2018 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-28954947

RESUMO

BACKGROUND: Excess of visceral fat is a central factor in the pathogenesis of metabolic syndrome (MetS) and atherosclerosis. However, little is known about how much epicardial fat affects cardiometabolic disorders in comparison with visceral or subcutaneous fat.Methods and Results:Participants suspected as having angina pectoris underwent cardiac computed tomography (CT) imaging. Of them, 374 subjects were analyzed the association of clinical characteristics and CT-based fat distribution measured as epicardial fat volume (EFV), visceral fat area (VFA), and subcutaneous fat area (SFA). EFV was highly associated with VFA (R=0.58). Serum adiponectin was significantly decreased in high VFA subjects (VFA ≥100 cm2) and was also reduced in the high EFV group (EFV ≥80 cm3). Among the low VFA groups, the numbers of subjects with diabetes and coronary atherosclerosis were increased in high EFV group. Among the low EFV groups, the numbers of subjects with diabetes, hyperuricemia, and coronary atherosclerosis were increased among the high VFA subjects. In an age-, sex-, and body mass index (BMI)-adjusted model, EFV was associated with dyslipidemia and MetS, and VFA was significantly associated with hypertension, dyslipidemia, MetS, and coronary atherosclerosis, while SFA was not related with coronary risks and atherosclerosis. CONCLUSIONS: Epicardial fat accumulation may be a risk for coronary atherosclerosis in subjects without visceral fat accumulation. Visceral fat is the strongest risk for cardiometabolic diseases among the 3 types of fat depot.


Assuntos
Doença da Artéria Coronariana/etiologia , Cardiopatias/metabolismo , Gordura Intra-Abdominal , Pericárdio/patologia , Gordura Subcutânea , Idoso , Feminino , Cardiopatias/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Tomografia Computadorizada por Raios X
16.
J Biol Chem ; 292(19): 7840-7849, 2017 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-28325833

RESUMO

Adiponectin, an adipocyte-derived circulating protein, accumulates in the heart, vascular endothelium, and skeletal muscles through an interaction with T-cadherin (T-cad), a unique glycosylphosphatidylinositol-anchored cadherin. Recent studies have suggested that this interaction is essential for adiponectin-mediated cardiovascular protection. However, the precise protein-protein interaction between adiponectin and T-cad remains poorly characterized. Using ELISA-based and surface plasmon analyses, we report here that T-cad fused with IgG Fc as a fusion tag by replacing its glycosylphosphatidylinositol-anchor specifically bound both hexameric and larger multimeric adiponectin with a dissociation constant of ∼1.0 nm and without any contribution from other cellular or serum factors. The extracellular T-cad repeats 1 and 2 were critical for the observed adiponectin binding, which is required for classical cadherin-mediated cell-to-cell adhesion. Moreover, the 130-kDa prodomain-bearing T-cad, uniquely expressed on the cell surface among members of the cadherin family and predominantly increased by adiponectin, contributed significantly to adiponectin binding. Inhibition of prodomain-processing by a prohormone convertase inhibitor increased 130-kDa T-cad levels and also enhanced adiponectin binding to endothelial cells both by more preferential cell-surface localization and by higher adiponectin-binding affinity of 130-kDa T-cad relative to 100-kDa T-cad. The preferential cell-surface localization of 130-kDa T-cad relative to 100-kDa T-cad was also observed in normal mice aorta in vivo In conclusion, our study shows that a unique key feature of the T-cad prodomain is its involvement in binding of the T-cad repeats 1 and 2 to adiponectin and also demonstrates that adiponectin positively regulates T-cad abundance.


Assuntos
Adiponectina/química , Caderinas/química , Adiponectina/genética , Animais , Células CHO , Cálcio/química , Adesão Celular , Membrana Celular/metabolismo , Cricetinae , Cricetulus , Dissulfetos/química , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Ensaio de Imunoadsorção Enzimática , Glicosilfosfatidilinositóis/química , Células HEK293 , Humanos , Imunoglobulina G/química , Cinética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ligação Proteica , Domínios Proteicos , Mapeamento de Interação de Proteínas , Ressonância de Plasmônio de Superfície
17.
FASEB J ; 31(4): 1571-1583, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28062540

RESUMO

Adiponectin, an adipocyte-derived protein abundant in the circulation, is thought to be protective against atherosclerosis. However, it is not fully understood how the association of adiponectin with vascular cells and its antiatherogenic effect are connected. In this study, T-cadherin was essential for accumulation of adiponectin in the neointima and atherosclerotic plaque lesions, and the adiponectin-T-cadherin association protected against vascular injury. In the apolipoprotein E-knockout (ApoE-KO) mice, adiponectin and T-cadherin colocalized on endothelial cells and synthetic smooth muscle cells in the aortic intima. Notably, aortic adiponectin protein disappeared in T-cadherin/ApoE double-knockout (Tcad/ApoE-DKO) mice with significant elevation of blood adiponectin concentration. Furthermore, in Tcad/ApoE-DKO mice, carotid artery ligation resulted in a significant increase of neointimal thickness compared with ApoE-KO mice. Finally, on a high-cholesterol diet, Tcad/ApoE-DKO mice increased atherosclerotic plaque formation, despite a 5-fold increase in plasma adiponectin level compared with that in ApoE-KO mice. In vitro, knockdown of T-cadherin from human aortic smooth muscle cells (HASMCs) with synthetic phenotype significantly reduced adiponectin accumulation on HASMCs and negated the inhibitory effect of adiponectin on proinflammatory change. Collective evidence showed that adiponectin accumulates in the vasculature via T-cadherin, and the adiponectin-T-cadherin association plays a protective role against neointimal and atherosclerotic plaque formations.-Fujishima, Y., Maeda, N., Matsuda, K., Masuda, S., Mori, T., Fukuda, S., Sekimoto, R., Yamaoka, M., Obata, Y., Kita, S., Nishizawa, H., Funahashi, T., Ranscht, B., Shimomura, I. Adiponectin association with T-cadherin protects against neointima proliferation and atherosclerosis.


Assuntos
Adiponectina/metabolismo , Aterosclerose/metabolismo , Caderinas/metabolismo , Adiponectina/sangue , Adiponectina/genética , Animais , Aterosclerose/patologia , Caderinas/genética , Proliferação de Células , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Túnica Íntima/metabolismo , Túnica Íntima/patologia
18.
Cardiovasc Diabetol ; 15(1): 159, 2016 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-27899146

RESUMO

BACKGROUND: Visceral fat plays a central role in the development of metabolic syndrome and atherosclerotic cardiovascular diseases. The association of visceral fat accumulation with cardio-metabolic diseases has been reported, but the impact of visceral fat on the gene expression profile in peripheral blood cells remains to be determined. The aim of this study was to determine the effects of visceral fat area (VFA) and subcutaneous fat area (SFA) on the gene expression profile in peripheral blood cells of obese subjects. METHODS: All 17 enrolled subjects were hospitalized to receive diet therapy for obesity (defined as body mass index, BMI, greater than 25 kg/m2). VFA and SFA were measured at the umbilical level by computed tomography (CT). Blood samples were subjected to gene expression profile analysis by using SurePrint G3 Human GE Microarray 8 × 60 k ver. 2.0. The correlation between various clinical parameters, including VFA and SFA, and peripheral blood gene expression levels was analyzed. RESULTS: Among the 17 subjects, 12 had normal glucose tolerance or borderline diabetes, and 5 were diagnosed with type 2 diabetes without medications [glycated hemoglobin (HbA1c); 6.3 ± 1.3%]. The mean BMI, VFA, and SFA were 30.0 ± 5.5 kg/m2, 177 ± 67 and 245 ± 131 cm2, respectively. Interestingly, VFA altered the expression of 1354 genes, including up-regulation of 307 and down-regulation of 1047, under the statistical environment that the parametric false discovery rate (FDR) was less than 0.1. However, no significant effects were noted for SFA or BMI. Gene ontology analysis showed higher prevalence of VFA-associated genes than that of SFA-associated genes, among the genes associated with inflammation, oxidative stress, immune response, lipid metabolism, and glucose metabolism. CONCLUSIONS: Accumulation of visceral fat, but not subcutaneous fat, has a significant impact on the gene expression profile in peripheral blood cells in obese Japanese subjects.


Assuntos
Adiposidade , Regulação da Expressão Gênica , Gordura Intra-Abdominal/fisiopatologia , Obesidade/genética , RNA/genética , Adiposidade/etnologia , Adulto , Idoso , Povo Asiático/genética , Índice de Massa Corporal , Biologia Computacional , Bases de Dados Genéticas , Feminino , Perfilação da Expressão Gênica/métodos , Marcadores Genéticos , Humanos , Gordura Intra-Abdominal/diagnóstico por imagem , Japão , Masculino , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/etnologia , Obesidade/fisiopatologia , Análise de Sequência com Séries de Oligonucleotídeos , RNA/sangue , Gordura Subcutânea/diagnóstico por imagem , Gordura Subcutânea/fisiopatologia , Tomografia Computadorizada por Raios X
19.
Intern Med ; 52(17): 1931-6, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23994986

RESUMO

A 59-year-old man with recurrent oral cancer presented with severe pancytopenia, hyponatremia and hypoglycemia. Endocrine testing showed a partial primary adrenal insufficiency and primary hypothyroidism. The bone marrow biopsy showed a gelatinous transformation with hypocellularity and fat atrophy. His pancytopenia, hyponatremia and hypoglycemia resolved following treatment with corticosteroids and thyroid hormone replacement therapy. The follow-up bone marrow biopsy demonstrated a resolution of the gelatinous transformation. This case is a rare example of a patient with a primary insufficiency of the adrenal and thyroid glands that is associated with gelatinous bone marrow transformation (GMT). The GMT was resolved through the administration of corticosteroids and thyroid hormone replacement therapy.


Assuntos
Doença de Addison/diagnóstico , Doenças da Medula Óssea/diagnóstico , Terapia de Reposição Hormonal/métodos , Hipotireoidismo/diagnóstico , Doença de Addison/complicações , Doença de Addison/tratamento farmacológico , Doenças da Medula Óssea/complicações , Doenças da Medula Óssea/tratamento farmacológico , Humanos , Hipotireoidismo/complicações , Hipotireoidismo/tratamento farmacológico , Masculino , Pessoa de Meia-Idade
20.
Clin Endocrinol (Oxf) ; 79(2): 204-10, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22963459

RESUMO

OBJECTIVE: Serum adiponectin levels are affected by gender, body fat mass, several pathological factors or therapeutic interventions and it might be also affected by age. This study aimed to investigate the relationship between serum adiponectin levels and age in several physiological states. DESIGN, PATIENTS AND MEASUREMENTS: The study was carried out in 21 100 healthy subjects (12 363 men and 8737 women) and 1833 patients with type 2 diabetes (1233 men and 600 women). Physical and demographic characteristics were recorded, and blood samples were collected to measure serum adiponectin levels. Using these data, we determined the relationships between serum adiponectin levels and various parameters, including age. RESULTS: Serum adiponectin levels increased with increasing age of healthy subjects and in patients with diabetes, in both men and women. Serum adiponectin levels were positively correlated with age in healthy subjects and patients with diabetes, in both men and women. In stepwise multiple regression analysis with serum adiponectin levels as the dependent variable and physiological characteristics as explanatory variables, age was significantly and independently associated with serum adiponectin levels in each of these groups of subjects. CONCLUSIONS: Serum adiponectin levels are significantly and positively associated with age in healthy subjects and in patients with diabetes. This association is independent of renal function, body fat status, glucose metabolism and lipid profiles.


Assuntos
Adiponectina/sangue , Diabetes Mellitus Tipo 2/sangue , Adulto , Fatores Etários , Idoso , Povo Asiático , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...