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AIMS: We assessed the potential efficacy and safety of propagermanium (PG), an organic compound that inhibits the C-C chemokine receptor type 2, administration in patients with type 2 diabetes and nephropathy. Furthermore, we assessed the feasibility of future studies. MATERIALS AND METHODS: We recruited patients from nine medical institutions in Japan for this randomized, open-label, parallel two-arm pilot trial. Inclusion criteria were diagnosis of type 2 diabetes, age 30-75 years, dipstick proteinuria of ≥1+ or urinary albumin-to-creatinine ratio (UACR) of ≥30 mg/g and estimated glomerular filtration rate of ≥30 mL/min/1.73 m2. Patients were randomly assigned (1:2) using a minimization algorithm to either continuing usual care or concomitant administration of 30 mg PG per day for 12 months. The primary outcome was the change in UACR from baseline to 12 months. We also collected safety information for all patients who received at least one dose of PG. RESULTS: We enrolled 29 patients, 10 were assigned to continue usual care and 19 to receive PG. Changes in UACR by PG in addition to the usual care were 25.0% (95% CI -20.4%, 96.5%, P = .33). No severe adverse events or renal events were observed during the study. CONCLUSION: Although the treatment with PG was generally well tolerated, the dosage of 30 mg/d for 12 months did not reduce albuminuria when used in addition to usual care in patients with type 2 diabetes and nephropathy. Efficacy of PG should be verified in future definitive trials.
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CONTEXT: Pseudohypoparathyroidism type 1b (PHP-1b) results from methylation defects at the G protein stimulatory α subunit (GNAS) exon A/B-differentially methylated region (DMR). Although microduplications in the GNAS region were recently identified in two PHP-1b patients, genetic information on these patients remained fragmentary. CASE DESCRIPTION: A 20-year-old Japanese male and his mother presented with hypocalcemia and elevated blood levels of intact PTH. The proband had a maternal uncle who was previously diagnosed with PHP-1b. Methylation-specific multiplex ligation-dependent probe amplification, array-based comparative genomic hybridization, pyrosequencing, fluorescence in situ hybridization, and whole-genome sequencing were performed for this family. The proband, mother, and uncle carried maternally derived approximately 133-kb duplication-triplication-duplication rearrangements at 20q13.32 involving NESP55, NESPAS, XLαs, and exon A/B-DMR but not STX16 or the Gsα coding region. These individuals exhibited partial methylation defects of NESP55-, NESPAS-, and XLαs-DMRs, which were ascribable to the increased copy numbers of these regions retaining the maternally derived methylation pattern and loss of methylation of exon A/B-DMR, which was inexplicable by the copy-number alterations. Fusion junctions of the rearrangement resided within non-repeat sequences and were accompanied by short-templated insertions. CONCLUSIONS: Our results indicate that maternally derived copy-number gains in the GNAS region mediated by nonhomologous end-joining and/or by break-induced replication can underlie autosomal dominant PHP-1b. These rearrangements likely affect methylation of exon A/B-DMR by disconnecting or disrupting its cis-acting regulator(s). This study provides a novel example of human disorders resulting from functional disturbance in the cis-regulatory machinery of DNA methylation.
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Cromograninas/genética , Aberraciones Cromosómicas , Subunidades alfa de la Proteína de Unión al GTP Gs/genética , Seudohipoparatiroidismo/genética , Adulto , Femenino , Humanos , Masculino , Madres , Núcleo Familiar , Seudohipoparatiroidismo/diagnóstico , Adulto Joven , SeudohipoparatiroidismoRESUMEN
PURPOSE: A step-up strategy for diet therapy and/or single oral antihyperglycemic agent (OHA) regimens has not yet been established. The aim of this study was to evaluate hemoglobin A1c (HbA1c) as a primary end point, and the pleiotropic effects on metabolic and cardiovascular parameters as secondary end points, of sitagliptin versus voglibose in patients with type 2 diabetes with inadequate glycemic control while on diet therapy and/or treatment with a single OHA. METHODS: In this multicenter, randomized, open-label, parallel-group trial, a total of 260 patients with inadequately controlled type 2 diabetes (HbA1c levels >6.9%) were randomly assigned to receive either sitagliptin (50â mg, once daily) or voglibose (0.6â mg, thrice daily) for 12â weeks. The primary end point was HbA1c levels. RESULTS: Patients receiving sitagliptin showed a significantly greater decrease in HbA1c levels (-0.78±0.69%) compared with those receiving voglibose (-0.30±0.78%). Sitagliptin treatment also lowered serum alkaline phosphatase levels and increased serum creatinine, uric acid, cystatin-C and homeostasis model assessment-ß values. Voglibose increased low-density lipoprotein-cholesterol levels and altered serum levels of several fatty acids, and increased Δ-5 desaturase activity. Both drugs increased serum adiponectin. The incidence of adverse events (AEs) was significantly lower in the sitagliptin group, due to the decreased incidence of gastrointestinal AEs. CONCLUSIONS: Sitagliptin shows superior antihyperglycemic effects compared with voglibose as a first-line or second-line therapy. However, both agents possess unique pleiotropic effects that lead to reduced cardiovascular risk in Japanese people with type 2 diabetes. TRIAL REGISTRATION NUMBER: UMIN 000003503.
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OBJECTIVE: The goal of this study was to examine whether metabolic abnormalities are responsible for the histological changes observed in Japanese patients with nonalcoholic fatty liver disease (NAFLD) who have undergone serial liver biopsies. RESEARCH DESIGN AND METHODS: In total, 39 patients had undergone consecutive liver biopsies. Changes in their clinical data were analyzed, and biopsy specimens were scored histologically for stage. RESULTS: The median follow-up time was 2.4 years (range 1.0-8.5). Liver fibrosis had improved in 12 patients (30.7%), progressed in 11 patients (28.2%), and remained unchanged in 16 patients (41%). In a Cox proportional hazard model, decrease in A1C and use of insulin were associated with improvement of liver fibrosis independent of age, sex, and BMI. However, DeltaA1C was more strongly associated with the improvement of liver fibrosis than use of insulin after adjustment for each other (chi(2); 7.97 vs. 4.58, respectively). CONCLUSIONS: Tight glycemic control may prevent histological progression in Japanese patients with NAFLD.
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Glucemia/metabolismo , Hígado Graso/terapia , Resistencia a la Insulina/fisiología , Cirrosis Hepática/prevención & control , Adulto , Anciano , Alanina Transaminasa/sangre , Aspartato Aminotransferasas/sangre , Biopsia , Índice de Masa Corporal , Progresión de la Enfermedad , Hígado Graso/sangre , Hígado Graso/complicaciones , Hígado Graso/patología , Femenino , Hemoglobina Glucada/metabolismo , Homeostasis , Humanos , Japón , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Pérdida de PesoRESUMEN
Tumor necrosis factor (TNF)-alpha and local activation of the renin-angiotensin system may contribute to insulin resistance and atherosclerosis. In this study, we investigated the involvement of these mediators in the liver. We found that the gene expression of renin-angiotensin system components, together with that of plasminogen activator inhibitor (PAI)-1, is upregulated in the liver of patients with obesity and type 2 diabetes. We next examined the role of the renin-angiotensin system on TNF-alpha-induced PAI-1 production in the nonmalignant human hepatocyte cell line THLE-5b. THLE-5b cells expressed genes encoding renin-angiotensin system components including angiotensinogen, angiotensin-converting enzyme (ACE), and angiotensin type 1 (AT(1)) receptor. ACE, angiotensinogen, and angiotensin AT(1) receptor mRNA expression were upregulated time-dependently by TNF-alpha. Moreover, angiotensin AT(1) receptor antagonist dose-dependently inhibited TNF-alpha-induced PAI-1 production. Interestingly, high-dose olmesartan, but not candesartan, reduced the increased expression of the angiotensin AT(1) receptor. These results suggest that TNF-alpha and the local renin-angiotensin system coordinately stimulate PAI-1 production in hepatocytes. Selective angiotensin AT(1) receptor antagonists inhibit both TNF-alpha- and angiotensin II-induced PAI-1 production in hepatocytes, suggesting a cross talk between both systems.
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Diabetes Mellitus Tipo 2/complicaciones , Obesidad/complicaciones , Inhibidor 1 de Activador Plasminogénico/metabolismo , Sistema Renina-Angiotensina/fisiología , Factor de Necrosis Tumoral alfa/metabolismo , Bloqueadores del Receptor Tipo 1 de Angiotensina II/administración & dosificación , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Línea Celular , Relación Dosis-Respuesta a Droga , Femenino , Regulación de la Expresión Génica , Hepatocitos/metabolismo , Humanos , Resistencia a la Insulina/fisiología , Hígado/metabolismo , Hígado/patología , Masculino , Persona de Mediana Edad , Inhibidor 1 de Activador Plasminogénico/genética , Transducción de Señal , Factores de TiempoRESUMEN
Plasminogen activator inhibitor 1 (PAI-1) is an important mediator of atherosclerosis and liver fibrosis in insulin resistance. Circulating levels of PAI-1 are elevated in obese individuals, and PAI-1 messenger RNA is significantly higher in the livers of obese type 2 diabetic individuals than in nonobese type 2 diabetic individuals. To address the mechanism underlying the up-regulation of hepatic PAI-1 in obesity, we tested the effects of tumor necrosis factor alpha (TNF-alpha), an important link between obesity and insulin resistance, on PAI-1 production in the nonmalignant human hepatocyte cell line, THLE-5b. Incubation of THLE-5b cells with TNF-alpha stimulated PAI-1 production via protein kinase C-, mitogen-activated protein kinase-, protein tyrosine kinase-, and nuclear factor-kappaB-dependent pathways. A thiazolidinedione, pioglitazone, reduced TNF-alpha-induced PAI-1 production by 32%, via protein kinase C- and nuclear factor-kappaB-dependent pathways. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor cerivastatin inhibited TNF-alpha-induced PAI-1 production by 59%, which was reversed by coincubation with mevalonic acid. In conclusion, obesity and TNF-alpha up-regulation of PAI-1 expression in human hepatocytes may contribute to the impairment of the fibrinolytic system, leading to the development of atherosclerosis and liver fibrosis in insulin-resistant individuals. A thiazolidinedione and a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor may thus be candidate drugs to inhibit obesity-associated hepatic PAI-1 production.
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Diabetes Mellitus Tipo 2/metabolismo , Hepatocitos/metabolismo , Obesidad/metabolismo , Inhibidor 1 de Activador Plasminogénico/biosíntesis , Piridinas/farmacología , Tiazolidinedionas/farmacología , Factor de Necrosis Tumoral alfa/farmacología , Línea Celular , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Hepatocitos/efectos de los fármacos , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Hipoglucemiantes/farmacología , Masculino , Persona de Mediana Edad , Pioglitazona , Inhibidor 1 de Activador Plasminogénico/genética , Inhibidor 1 de Activador Plasminogénico/metabolismo , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/efectos de los fármacos , Activador de Tejido Plasminógeno/genética , Activador de Tejido Plasminógeno/metabolismo , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
A 34-year-old woman was referred to our hospital complaining of sore throat and arthralgia. She had low-grade fever, tachycardia, and goiter with tenderness. Laboratory data revealed thyrotoxicosis and tests for acute inflammatory markers were positive. Thyroidal radioactive iodine uptake was below normal. Ultrasonography of thyroid revealed mild thyroid enlargement and hypoechogenic areas consistent with tenderness. Subacute thyroiditis was diagnosed and prednisone was administered. Two years later, her identical twin sister, who lives separately, was referred to our hospital because of neck pain, low-grade fever, and palpitation. She exhibited the same clinical picture as her twin sister, and was also diagnosed as having subacute thyroiditis. Although the cause of subacute thyroiditis remains unclear, viral infection has been implicated in the onset of subacute thyroiditis in genetically predisposed individuals. We could not identify the viruses, but heterozygotes for HLA-B35, which has been reported to be linked with subacute thyroiditis, were found in the twins. This supports the suspicion that genetic factors, including this HLA haplotype, play a critical role in the onset of subacute thyroiditis.
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Enfermedades en Gemelos/genética , Tiroiditis Subaguda/genética , Gemelos Monocigóticos , Adulto , Femenino , Predisposición Genética a la Enfermedad , Antígeno HLA-B35/genética , HumanosRESUMEN
Plasminogen activator inhibitor type 1 (PAI-1) plays a role in the development of atherosclerosis in diabetic patients. PAI-1 is produced by endothelial cells stimulated with various inflammatory cytokines, such as tumor necrosis factor (TNF)-alpha, which induces insulin resistance. In diabetic patients, troglitazone, a thiazolidinedione, can lower the concentration of PAI-1. We investigated the TNF-alpha-induced signaling pathway that leads to PAI-1 synthesis and the target step of troglitazone in this pathway. TNF-alpha induced PAI-1 mRNA expression and protein production in human umbilical vein endothelial cells (HUVECs). A specific inhibitor for p38 mitogen-activated protein kinase, 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB 203580), and a protein kinase C inhibitor, calphostin C, had no inhibitory effects on TNF-alpha-induced PAI-1 secretion. A protein tyrosine kinase inhibitor, genistein, completely inhibited TNF-alpha-induced PAI-1 secretion, whereas an inhibitor of extracellular signal-regulated kinase (ERK) kinase, 2'-amino-3'-methoxyflavone (PD98059), and a nuclear factor-kappaB (NF-kappaB) inhibitor, emodin, partly inhibited TNF-alpha-induced PAI-1 secretion. Together, PD98059 and emodin completely inhibited TNF-alpha-induced PAI-1 secretion, suggesting that both NF-kappaB-dependent and NF-kappaB-independent pathways are involved in TNF-alpha-induced signal pathway to PAI-1 production and that the latter pathway is mediated by activation of ERK. Furthermore, we have shown that troglitazone inhibited both TNF-alpha-induced PAI-1 protein secretion and mRNA in HUVECs. Genistein, but neither PD98059 nor emodin, was additive to the inhibitory effect of troglitazone on TNF-alpha-induced PAI-1 secretion. These results indicate That ERK and NF-kappaB are possible targets of TNF-alpha and troglitazone in the regulation of PAI-1 production.