RESUMEN
Orthostatic hypotension (OH) is a common condition. Many potential etiologies of OH have been identified, but in clinical practice the underlying cause of OH is often unknown. In the present study, we identified a novel and extraordinary etiology of OH. We describe a first case of acquired severe OH with syncope, and the female patient had extremely low levels of catecholamines and serotonin in plasma, urine and cerebrospinal fluid (CSF). Her clinical and biochemical evidence showed a deficiency of the enzyme aromatic l-amino acid decarboxylase (AADC), which converts l-DOPA to dopamine, and 5-hydroxytryptophan to serotonin, respectively. The consequence of pharmacologic stimulation of catecholaminergic nerves and radionuclide examination revealed her catecholaminergic nerves denervation. Moreover, we found that the patient's serum showed presence of autoantibodies against AADC, and that isolated peripheral blood mononuclear cells (PBMCs) from the patient showed cytokine-induced toxicity against AADC. These observations suggest that her autoimmunity against AADC is highly likely to cause toxicity to adrenal medulla and catecholaminergic nerves which contain AADC, resulting in hypocatecholaminemia and severe OH. Administration of vitamin B6, an essential cofactor of AADC, enhanced her residual AADC activity and drastically improved her symptoms. Our data thus provide a new insight into pathogenesis and pathophysiology of OH.
Asunto(s)
Descarboxilasas de Aminoácido-L-Aromático , Autoinmunidad , Hipotensión Ortostática , Femenino , Humanos , Persona de Mediana Edad , Descarboxilasas de Aminoácido-L-Aromático/deficiencia , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Catecolaminas , Dopamina/metabolismo , Hipotensión Ortostática/etiología , Hipotensión Ortostática/fisiopatología , Serotonina/metabolismoRESUMEN
Both high-fat (HFD) and high-carbohydrate (ST) diets are known to induce weight gain. Glucose-dependent insulinotropic polypeptide (GIP) is secreted mainly from intestinal K cells upon stimuli by nutrients such as fat and glucose, and it potentiates glucose-induced insulin secretion. GIP is well known to contribute to HFD-induced obesity. In this study, we analyzed the effect of ST feeding on GIP secretion and metabolic parameters to explore the role of GIP in ST-induced weight gain. Both wild-type (WT) and GIP receptor deficient ( GiprKO) mice were fed normal chow (NC), ST, or moderate (m)HFD for 22 wk. Body weight was measured, and then glucose tolerance tests were performed. Insulin secretion from isolated islets also was analyzed. WT mice fed ST or mHFD displayed weight gain concomitant with increased plasma GIP levels compared with WT mice fed NC. WT mice fed mHFD showed improved glucose tolerance due to enhanced insulin secretion during oral glucose tolerance tests compared with WT mice fed NC or ST. GiprKO mice fed mHFD did not display weight gain. On the other hand, GiprKO mice fed ST showed weight gain and did not display obvious glucose intolerance. Glucose-induced insulin secretion was enhanced during intraperitoneal glucose tolerance tests and from isolated islets in both WT and GiprKO mice fed ST compared with those fed NC. In conclusion, enhanced GIP secretion induced by mHFD-feeding contributes to increased insulin secretion and body weight gain, whereas GIP is marginally involved in weight gain induced by ST-feeding.
Asunto(s)
Dieta Alta en Grasa/efectos adversos , Grasas de la Dieta/farmacología , Polipéptido Inhibidor Gástrico/fisiología , Aumento de Peso/efectos de los fármacos , Animales , Carbohidratos de la Dieta/efectos adversos , Glucosa/metabolismo , Intolerancia a la Glucosa/genética , Intolerancia a la Glucosa/metabolismo , Prueba de Tolerancia a la Glucosa/métodos , Insulina/metabolismo , Resistencia a la Insulina/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de la Hormona Gastrointestinal/genética , Receptores de la Hormona Gastrointestinal/metabolismoRESUMEN
Clozapine, a second-generation antipsychotic (SGA), is a cause of side effects related to metabolic syndrome. The participation of serotonin 5-HT2C and histamine H1 receptors in the central nervous system has been reported as a mechanism of the weight gain caused by clozapine. In the present study, we investigated the direct pharmacological action of clozapine on the 3T3-L1 adipocytes and compared it to that of blonanserin, an SGA with low affinity for both receptors. Short-term exposure to clozapine decreased secretion and mRNA expression of leptin. Long-term exposure decreased leptin as well as adiponectin secretion, and further increased lipid droplets accumulation. However, short- and long-term exposures to blonanserin did not affect these parameters. A selective serotonin 5-HT2C, but not a histamine H1, receptor antagonist enhanced the decreased secretion of leptin induced by short-term exposure to clozapine, but did not affect the increased accumulation of lipid droplets. Our findings indicate that clozapine, but not blonanserin, strongly and directly affected the secretion of adipokines, such as leptin, in adipocytes and caused adipocyte enlargement.
Asunto(s)
Adipocitos/efectos de los fármacos , Adiponectina/metabolismo , Clozapina/efectos adversos , Leptina/metabolismo , Gotas Lipídicas/metabolismo , Células 3T3-L1 , Animales , Antipsicóticos/efectos adversos , Antipsicóticos/farmacología , Supervivencia Celular , Clozapina/farmacología , Ratones , Piperazinas/efectos adversos , Piperazinas/metabolismo , Piperazinas/farmacología , Piperidinas/efectos adversos , Piperidinas/metabolismo , Piperidinas/farmacologíaRESUMEN
The adenohypophysis (anterior pituitary) is a major centre for systemic hormones. At present, no efficient stem-cell culture for its generation is available, partly because of insufficient knowledge about how the pituitary primordium (Rathke's pouch) is induced in the embryonic head ectoderm. Here we report efficient self-formation of three-dimensional adenohypophysis tissues in an aggregate culture of mouse embryonic stem (ES) cells. ES cells were stimulated to differentiate into non-neural head ectoderm and hypothalamic neuroectoderm in adjacent layers within the aggregate, and treated with hedgehog signalling. Self-organization of Rathke's-pouch-like three-dimensional structures occurred at the interface of these two epithelia, as seen in vivo, and various endocrine cells including corticotrophs and somatotrophs were subsequently produced. The corticotrophs efficiently secreted adrenocorticotropic hormone in response to corticotrophin releasing hormone and, when grafted in vivo, these cells rescued the systemic glucocorticoid level in hypopituitary mice. Thus, functional anterior pituitary tissue self-forms in ES cell culture, recapitulating local tissue interactions.
Asunto(s)
Células Madre Embrionarias/citología , Adenohipófisis/citología , Adenohipófisis/embriología , Animales , Técnicas de Cultivo de Célula , Línea Celular , Linaje de la Célula , Células Cultivadas , Ectodermo/citología , Ectodermo/embriología , Células Endocrinas/citología , Células Endocrinas/metabolismo , Hipopituitarismo/patología , Hipotálamo/citología , Hipotálamo/embriología , RatonesRESUMEN
Hyponatremia is the most common clinical electrolyte disorder. Once thought to be asymptomatic in response to adaptation by the brain, recent evidence suggests that chronic hyponatremia may be linked to attention deficits, gait disturbances, risk of falls, and cognitive impairments. Such neurologic defects are associated with a reduction in quality of life and may be a significant cause of mortality. However, because underlying diseases such as adrenal insufficiency, heart failure, liver cirrhosis, and cancer may also affect brain function, the contribution of hyponatremia alone to neurologic manifestations and the underlying mechanisms remain unclear. Using a syndrome of inappropriate secretion of antidiuretic hormone rat model, we show here that sustained reduction of serum sodium ion concentration induced gait disturbances; facilitated the extinction of a contextual fear memory; caused cognitive impairment in a novel object recognition test; and impaired long-term potentiation at hippocampal CA3-CA1 synapses. In vivo microdialysis revealed an elevated extracellular glutamate concentration in the hippocampus of chronically hyponatremic rats. A sustained low extracellular sodium ion concentration also decreased glutamate uptake by primary astrocyte cultures, suggesting an underlying mechanism of impaired long-term potentiation. Furthermore, gait and memory performances of corrected hyponatremic rats were equivalent to those of control rats. Thus, these results suggest chronic hyponatremia in humans may cause gait disturbance and cognitive impairment, but these abnormalities are reversible and careful correction of this condition may improve quality of life and reduce mortality.
Asunto(s)
Trastornos Neurológicos de la Marcha/etiología , Hiponatremia/complicaciones , Síndrome de Secreción Inadecuada de ADH/fisiopatología , Trastornos de la Memoria/etiología , Animales , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Región CA1 Hipocampal/fisiopatología , Región CA3 Hipocampal/fisiopatología , Células Cultivadas , Enfermedad Crónica , Trastornos del Conocimiento/sangre , Trastornos del Conocimiento/etiología , Modelos Animales de Enfermedad , Miedo/fisiología , Trastornos Neurológicos de la Marcha/sangre , Ácido Glutámico/metabolismo , Hiponatremia/sangre , Hiponatremia/psicología , Síndrome de Secreción Inadecuada de ADH/complicaciones , Síndrome de Secreción Inadecuada de ADH/psicología , Masculino , Trastornos de la Memoria/sangre , Microdiálisis , Plasticidad Neuronal , Ratas , Ratas Sprague-Dawley , Sodio/sangre , Sodio/farmacología , Sinapsis/fisiologíaRESUMEN
AIMS/HYPOTHESIS: The action of incretin hormones including glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) is potentiated in animal models defective in glucagon action. It has been reported that such animal models maintain normoglycaemia under streptozotocin (STZ)-induced beta cell damage. However, the role of GIP in regulation of glucose metabolism under a combination of glucagon deficiency and STZ-induced beta cell damage has not been fully explored. METHODS: In this study, we investigated glucose metabolism in mice deficient in proglucagon-derived peptides (PGDPs)-namely glucagon gene knockout (GcgKO) mice-administered with STZ. Single high-dose STZ (200 mg/kg, hSTZ) or moderate-dose STZ for five consecutive days (50 mg/kg × 5, mSTZ) was administered to GcgKO mice. The contribution of GIP to glucose metabolism in GcgKO mice was also investigated by experiments employing dipeptidyl peptidase IV (DPP4) inhibitor (DPP4i) or Gcg-Gipr double knockout (DKO) mice. RESULTS: GcgKO mice developed severe diabetes by hSTZ administration despite the absence of glucagon. Administration of mSTZ decreased pancreatic insulin content to 18.8 ± 3.4 (%) in GcgKO mice, but ad libitum-fed blood glucose levels did not significantly increase. Glucose-induced insulin secretion was marginally impaired in mSTZ-treated GcgKO mice but was abolished in mSTZ-treated DKO mice. Although GcgKO mice lack GLP-1, treatment with DPP4i potentiated glucose-induced insulin secretion and ameliorated glucose intolerance in mSTZ-treated GcgKO mice, but did not increase beta cell area or significantly reduce apoptotic cells in islets. CONCLUSIONS/INTERPRETATION: These results indicate that GIP has the potential to ameliorate glucose intolerance even under STZ-induced beta cell damage by increasing insulin secretion rather than by promoting beta cell survival.
Asunto(s)
Polipéptido Inhibidor Gástrico/metabolismo , Insulina/metabolismo , Proglucagón/metabolismo , Animales , Apoptosis/genética , Apoptosis/fisiología , Diabetes Mellitus Experimental/metabolismo , Modelos Animales de Enfermedad , Células Secretoras de Insulina/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proglucagón/deficiencia , Estreptozocina/toxicidadRESUMEN
Chronic kidney disease (CKD) is a cause of coronary artery calcification (CAC) and an independent predictor of major adverse cardiac and cerebrovascular events (MACCE). Cathepsin K (CatK) is a lysosomal cysteine protease which affects vascular calcification and glucose metabolism disorder. We investigated the relationships among CatK, CAC, diabetes mellitus (DM) and MACCE in CKD patients. 113 consecutive CKD patients were enrolled. Their CAC was evaluated by computed tomography. Their plasma CatK level was measured by ELISA. They were divided into two groups by CatK levels and followed up for up to 3 years. The impact of CatK was analyzed in all participants, diabetic patients and non-diabetic patients. Kaplan-Meier analysis demonstrated a significant higher incidence of MACCE in the high CatK group (P = 0.028). The CatK level was significantly higher in patients with MACCE compared to that in patients without MACCE (P = 0.034). Cox's model revealed the higher plasma CatK and BNP level as independent predictors of MACCE (P = 0.043 and P < 0.01, respectively). Only in non-diabetic patients, there was a significant correlation between CatK and CAC score, and high CatK group had a significant higher level of LDL-C and LDL-C/HDL-C ratio (P < 0.05 and P < 0.001, respectively) than low CatK group. And these lipid disorders were independent predictors of CatK elevation. In CKD patients, our results indicated an impact of higher CatK level on their MACCE. The significant association among the CatK level, CAC and MACCE was found in non-diabetic CKD patients.
Asunto(s)
Catepsina K/sangre , Enfermedad de la Arteria Coronaria/sangre , Diabetes Mellitus/sangre , Péptido Natriurético Encefálico/sangre , Insuficiencia Renal Crónica/complicaciones , Calcificación Vascular/sangre , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Japón , Estimación de Kaplan-Meier , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Modelos de Riesgos Proporcionales , Factores de Riesgo , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: The clinical usefulness of physiological and radiological examinations for cardiovascular disease (CVD) risk stratification has not been fully demonstrated in chronic kidney disease (CKD) patients. In the present study, predictive values of CVD were investigated among asymptomatic CKD patients by comprehensive and non-invasive CVD screening programs. METHODS: We prospectively evaluated 139 asymptomatic CKD patients. All patients were examined by comprehensive and non-invasive CVD risk screening programs that included carotid ultrasonography, coronary artery calcification score (CACS), pulse wave velocity, and flow-mediated vasodilation, and their associations with major adverse cardiovascular events (MACEs) were analyzed. RESULTS: During the median follow-up of 32.3 months, 13 MACEs were observed. Among all CVD screening examinations, severity of the carotid plaque score (PS) and CACS was significantly higher in the MACE group than in the MACE-free group (11.3 ± 5.8 versus 6.1 ± 5.3, P = 0.001 and 657 versus 74, P = 0.020, respectively). Kaplan-Meier curves for the incidences of MACEs classified according to the combination of carotid PS and CACS showed that severe carotid PS and severe CACS groups had the highest event rate in comparison with the groups without any of these (29.9, 11.9, and 3.6 %, respectively, P < 0.001). CONCLUSIONS: In this long-term follow-up analysis, the combination of carotid atherosclerosis and CACS was a useful and non-invasive screening tool for predicting cardiovascular events among asymptomatic CKD patients.
Asunto(s)
Enfermedades de las Arterias Carótidas/diagnóstico , Enfermedad de la Arteria Coronaria/diagnóstico , Técnicas de Diagnóstico Cardiovascular , Insuficiencia Renal Crónica/diagnóstico , Calcificación Vascular/diagnóstico , Anciano , Anciano de 80 o más Años , Enfermedades Asintomáticas , Enfermedades de las Arterias Carótidas/epidemiología , Enfermedades de las Arterias Carótidas/fisiopatología , Distribución de Chi-Cuadrado , Enfermedad de la Arteria Coronaria/epidemiología , Enfermedad de la Arteria Coronaria/fisiopatología , Supervivencia sin Enfermedad , Femenino , Humanos , Incidencia , Japón/epidemiología , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Insuficiencia Renal Crónica/epidemiología , Insuficiencia Renal Crónica/fisiopatología , Medición de Riesgo , Factores de Riesgo , Índice de Severidad de la Enfermedad , Factores de Tiempo , Calcificación Vascular/epidemiología , Calcificación Vascular/fisiopatologíaRESUMEN
Compared with other cancers, diabetes mellitus is more closely associated with hepatocellular carcinoma (HCC). However, whether hyperglycemia is associated with hepatic carcinogenesis remains uncertain. In this study, we investigate the effect of hyperglycemia on HCC development. Mice pretreated with 7,12-dimethylbenz (a) anthracene were divided into three feeding groups: normal diet (Control), high-starch diet (Starch), and high-fat diet (HFD) groups. In addition, an STZ group containing mice that were fed a normal diet and injected with streptozotosin to induce hyperglycemia was included. The STZ group demonstrated severe hyperglycemia, whereas the Starch group demonstrated mild hyperglycemia and insulin resistance. The HFD group demonstrated mild hyperglycemia and severe insulin resistance. Multiple HCC were macroscopically and histologically observed only in the HFD group. Hepatic steatosis was observed in the Starch and HFD groups, but levels of inflammatory cytokines, interleukin (IL)-6, tumor necrosis factor-α, and IL-1ß, were elevated only in the HFD group. The composition of gut microbiota was similar between the Control and STZ groups. A significantly higher number of Clostridium cluster XI was detected in the feces of the HFD group than that of all other groups; it was not detectable in the Starch group. These data suggested that hyperglycemia had no effect on hepatic carcinogenesis. Different incidences of HCC between the Starch and HFD groups may be attributable to degree of insulin resistance, but diet-induced changes in gut microbiota including Clostridium cluster XI may have influenced hepatic carcinogenesis. In conclusion, in addition to the normalization of blood glucose levels, diabetics may need to control insulin resistance and diet contents to prevent HCC development.
Asunto(s)
Carcinoma Hepatocelular/etiología , Diabetes Mellitus Experimental/complicaciones , Hiperglucemia/complicaciones , Neoplasias Hepáticas/etiología , Animales , Carcinoma Hepatocelular/microbiología , Carcinoma Hepatocelular/patología , Clostridium/aislamiento & purificación , Diabetes Mellitus Experimental/microbiología , Dieta/efectos adversos , Dieta Alta en Grasa/efectos adversos , Hígado Graso/etiología , Hígado Graso/microbiología , Hígado Graso/patología , Tracto Gastrointestinal/microbiología , Hiperglucemia/microbiología , Hiperglucemia/patología , Resistencia a la Insulina , Hígado/patología , Neoplasias Hepáticas/microbiología , Neoplasias Hepáticas/patología , Masculino , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: Hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome is a rare autosomal dominant disorder caused by mutations in the zinc finger transcription factor gene, GATA3. GATA3 has 2 zinc finger domains, which play an important role in the increase in target gene transcription activity. CASE PRESENTATION: A 50-year-old woman and her 27-year-old daughter were followed up because of hypoparathyroidism. They had bilateral sensorineural deafness. Abdominal computed tomography scanning revealed renal dysplasia in the mother, but no renal anomaly in the daughter. Direct sequencing of GATA3 gene revealed a novel heterozygous missense mutation at codon 299 (p.R299Q) in exon 4. This mutation is located at the junction between the 2 zinc fingers. The structure prediction showed that it caused a conformation change in this junction area, affecting the spatial position of the zinc fingers. Additionally, a more marked conformation change was observed in the N-terminal zinc finger region compared to that in the C-terminal region. Functional analysis of this mutant protein using an in vitro luciferase reporter assay system confirmed that the mutation abolished the enhancing effects of wild-type GATA3 on the promoter activity of the consensus GATA responsive element and that of human PTH gene. CONCLUSION: We identified a novel R299Q mutation in GATA3 in a Japanese family with HDR syndrome. We confirmed that R299Q is a loss-of-function mutation, due to the extensive conformational change in the zinc fingers of GATA3.
Asunto(s)
Sordera/complicaciones , Factor de Transcripción GATA3/genética , Hipoparatiroidismo/complicaciones , Riñón/anomalías , Mutación/genética , Sordera/genética , Sordera/patología , Familia , Femenino , Humanos , Hipoparatiroidismo/genética , Hipoparatiroidismo/patología , Persona de Mediana Edad , Pronóstico , SíndromeRESUMEN
BACKGROUND: Several studies have demonstrated that spironolactone has an anti-albuminuric property in diabetic nephropathy. As an adverse event, spironolactone often induces the elevation of creatinine levels with hypotension and hyperkalemia. Therefore, we aimed to evaluate the efficacy and safety of spironolactone in Japanese patients with type 2 diabetes treated with either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. METHODS: Fifty-two Japanese patients with diabetic nephropathy and albuminuria (100 mg/gCr-2000 mg/gCr) treated with renin-angiotensin system (RAS) blockade were enrolled in a prospective, randomized, open-label study. The patients were subjected to add-on treatment with spironolactone 25 mg once daily and compared with matched controls for 8 weeks. The primary outcome was a reduction in the rate of albuminuria at 8 weeks compared with the baseline value. This study was registered with UMIN Clinical Trials Registry (000008016). RESULTS: Albuminuria was reduced by 33 % (95 % confidence interval: 22-54; P = 0.0002) at 8 weeks with spironolactone. In the spironolactone group, blood pressure tended to lower and the estimated glomerular filtration rate (eGFR) was significantly decreased compared to those in the control group. When adjusted by systolic blood pressure and eGFR, spironolactone treatment still showed a significant effect on albuminuria reduction in a linear mixed model (coefficient ± standard error; 514.4 ± 137.6 mg/gCr, P < 0.0005). No patient was excluded from the study because of hyperkalemia. CONCLUSIONS: Spironolactone reduced albuminuria along with conventional RAS inhibitors in patients with diabetic nephropathy. Our study suggests that spironolactone exerts anti-albuminuric effects independent of systemic hemodynamic alterations.
Asunto(s)
Albuminuria/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/orina , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Espironolactona/uso terapéutico , Adulto , Anciano , Albuminuria/complicaciones , Aldosterona/sangre , Pueblo Asiatico , Presión Sanguínea/efectos de los fármacos , Diabetes Mellitus Tipo 2/orina , Femenino , Tasa de Filtración Glomerular/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Antagonistas de Receptores de Mineralocorticoides/efectos adversos , Estudios Prospectivos , Espironolactona/efectos adversos , Resultado del TratamientoRESUMEN
Central diabetes insipidus (CDI), which is characterized by polyuria and polydipsia, is caused by a deficiency of the antidiuretic hormone arginine vasopressin (AVP). While CDI is treated with desmopressin, an analogue of AVP, the intranasal formulation is inconvenient and CDI patients reportedly prefer the oral formulation to the intranasal one. In Japan, intranasal desmopressin had been the only formulation for the treatment of CDI until 2012, when the desmopressin orally disintegrating tablet (ODT) was approved for treatment. In this study we analyzed 26 patients with CDI in whom intranasal desmopressin was switched to desmopressin ODT. The mean daily dose of intranasal desmopressin was 10 ± 8 µg/day, and that of desmopressin ODT was 142 ± 59 µg/day. The mean serum sodium levels were 140 ± 5 mmol/L and 140 ± 3 mmol/L with intranasal desmopressin and desmopressin ODT, respectively, and there were no significant differences between these values. The frequency of hyponatremia (<135 mmol/L) with intranasal desmopressin was 11.7% and that with desmopressin ODT was 7.6%, while the frequency of hyponatremia (<130 mmol/L) with intranasal desmopressin was 4.2% and that with desmopressin ODT was 1.3%. Statistical analyses revealed that incidence of hyponatremia was significantly decreased after the switch to desmopressin ODT. Thus, it is suggested that water balance is better controlled with desmopressin ODT than with intranasal desmopressin in patients with CDI.
Asunto(s)
Fármacos Antidiuréticos/administración & dosificación , Desamino Arginina Vasopresina/administración & dosificación , Diabetes Insípida Neurogénica/tratamiento farmacológico , Hiponatremia/prevención & control , Administración Intranasal , Administración Oral , Adolescente , Adulto , Anciano , Fármacos Antidiuréticos/efectos adversos , Fármacos Antidiuréticos/uso terapéutico , Niño , Preescolar , Desamino Arginina Vasopresina/efectos adversos , Desamino Arginina Vasopresina/uso terapéutico , Aprobación de Drogas , Monitoreo de Drogas , Registros Electrónicos de Salud , Femenino , Hospitales Universitarios , Humanos , Hiponatremia/inducido químicamente , Hiponatremia/epidemiología , Incidencia , Japón/epidemiología , Masculino , Persona de Mediana Edad , Riesgo , Adulto JovenRESUMEN
Isolated adrenocorticotropin deficiency (IAD) is characterized by low or absent adrenocorticotropic hormone (ACTH) production. IAD is presumed to be caused in part by an autoimmune mechanism, and several lines of evidence have suggested the presence of anti-pituitary antibodies in IAD. However, the exact autoantigens remain unknown. The present study was designed to identify the autoantigen(s) in IAD using chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Rat anterior pituitary lysate was subjected to SDS-PAGE, and immunoblotting was performed using the sera from two patients with IAD and from a healthy subject. The bands detected by the patient serum samples, but not by the healthy subject sample, were excised, in-gel digested using trypsin, and subjected to LC-MS/MS analysis. On immunoblots, a 51-kDa band in the insoluble pellet was detected by the sera from the IAD patients but not from the healthy subject. Mass spectrometric analysis revealed the 51-kDa band contained Rab guanine nucleotide dissociation inhibitor (GDI) alpha. Consistent with the mass spectrometric analysis, a recombinant full-length human Rab GDI alpha was recognized by the two IAD patient samples but not by the healthy subject sample using immunoblotting. In total, anti-Rab GDI alpha antibodies were detected in serum samples from three of five patients with IAD (60%) but were absent in 5 healthy subjects. In addition, Rab GDI alpha was expressed in the anterior pituitary. In conclusion, it appears that Rab GDI alpha is a candidate autoantigen involved in IAD, and that anti-Rab GDI alpha antibodies are present predominantly in patients with IAD.
Asunto(s)
Hormona Adrenocorticotrópica/deficiencia , Autoanticuerpos/análisis , Autoantígenos/metabolismo , Enfermedades Autoinmunes/metabolismo , Autoinmunidad , Enfermedades del Sistema Endocrino/metabolismo , Enfermedades Genéticas Congénitas/metabolismo , Inhibidores de Disociación de Guanina Nucleótido/metabolismo , Hipoglucemia/metabolismo , Adenohipófisis/metabolismo , Hormona Adrenocorticotrópica/sangre , Hormona Adrenocorticotrópica/inmunología , Hormona Adrenocorticotrópica/metabolismo , Adulto , Anciano , Animales , Especificidad de Anticuerpos , Autoantígenos/química , Autoantígenos/genética , Enfermedades Autoinmunes/sangre , Enfermedades Autoinmunes/inmunología , Enfermedades del Sistema Endocrino/sangre , Enfermedades del Sistema Endocrino/inmunología , Femenino , Enfermedades Genéticas Congénitas/sangre , Enfermedades Genéticas Congénitas/inmunología , Inhibidores de Disociación de Guanina Nucleótido/química , Inhibidores de Disociación de Guanina Nucleótido/genética , Humanos , Hipoglucemia/sangre , Hipoglucemia/inmunología , Japón , Masculino , Persona de Mediana Edad , Peso Molecular , Mapeo Peptídico , Adenohipófisis/inmunología , Ratas Sprague-Dawley , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Homología de Secuencia de Aminoácido , Organismos Libres de Patógenos EspecíficosRESUMEN
There is evidence suggesting that the GABA system in the arcuate nucleus, where orexigenic neuropeptide Y and agouti-related peptide as well as anorexigenic proopiomelanocortin (POMC) are expressed, plays an important role in energy balance. In this study, we generated POMC-specific GABAB receptor-deficient [knock-out (KO)] mice. Male KO mice on a high-fat diet (HFD) showed mild increases in body weight (BW) at the age of 9 weeks compared to wild-type (WT) mice, and the differences remained significant until 16 weeks old. However, there was no difference in BW in females between genotypes. While food intake was similar between genotypes, oxygen consumption was significantly decreased in the male KO mice. The insulin tolerance test revealed that the male KO mice were less insulin sensitive compared to WT mice at the age of 8 weeks, when there was no significant difference in BW between genotypes. Despite increased BW, POMC mRNA expression in the arcuate nucleus was significantly decreased in the KO mice compared to WT mice at the age of 16 weeks. Furthermore, the expression of TNFα as well as IL-6, proinflammatory markers in the hypothalamus, was significantly increased in the KO mice on a HFD compared to WT mice. This demonstrates that the deletion of GABAB receptors in POMC neurons in the male mice on a HFD results in obesity, insulin resistance, and hypothalamic inflammation. Furthermore, the decreased POMC expression in the obese KO mice suggests that the regulation of POMC expression through GABAB receptors is essential for proper energy balance.
Asunto(s)
Núcleo Arqueado del Hipotálamo/metabolismo , Dieta Alta en Grasa , Inflamación/metabolismo , Resistencia a la Insulina , Obesidad/metabolismo , Receptores de GABA-B/metabolismo , Transducción de Señal , Animales , Ingestión de Alimentos , Metabolismo Energético , Femenino , Eliminación de Gen , Genotipo , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Ratones , Obesidad/etiología , Obesidad/genética , Proopiomelanocortina/genética , Proopiomelanocortina/metabolismo , Receptores de GABA-B/genética , Factores Sexuales , Transcripción Genética , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo , Aumento de PesoRESUMEN
Actin dynamics in pancreatic ß-cells is involved in insulin secretion. However, the molecular mechanisms of the regulation of actin dynamics by intracellular signals in pancreatic ß-cells and its role in phasic insulin secretion are largely unknown. In this study, we elucidate the regulation of actin dynamics by neuronal Wiskott-Aldrich syndrome protein (N-WASP) and cofilin in pancreatic ß-cells and demonstrate its role in glucose-induced insulin secretion (GIIS). N-WASP, which promotes actin polymerization through activation of the actin nucleation factor Arp2/3 complex, was found to be activated by glucose stimulation in insulin-secreting clonal pancreatic ß-cells (MIN6-K8 ß-cells). Introduction of a dominant-negative mutant of N-WASP, which lacks G-actin and Arp2/3 complex-binding region VCA, into MIN6-K8 ß-cells or knockdown of N-WASP suppressed GIIS, especially the second phase. We also found that cofilin, which severs F-actin in its dephosphorylated (active) form, is converted to the phosphorylated (inactive) form by glucose stimulation in MIN6-K8 ß-cells, thereby promoting F-actin remodeling. In addition, the dominant-negative mutant of cofilin, which inhibits activation of endogenous cofilin, or knockdown of cofilin reduced the second phase of GIIS. However, the first phase of GIIS occurs in the G-actin predominant state, in which cofilin activity predominates over N-WASP activity. Thus, actin dynamics regulated by the balance of N-WASP and cofilin activities determines the biphasic response of GIIS.
Asunto(s)
Factores Despolimerizantes de la Actina/metabolismo , Glucosa/farmacología , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Edulcorantes/farmacología , Proteína Neuronal del Síndrome de Wiskott-Aldrich/metabolismo , Factores Despolimerizantes de la Actina/genética , Complejo 2-3 Proteico Relacionado con la Actina/genética , Complejo 2-3 Proteico Relacionado con la Actina/metabolismo , Actinas/genética , Actinas/metabolismo , Animales , Línea Celular , Técnicas de Silenciamiento del Gen , Humanos , Insulina/genética , Secreción de Insulina , Células Secretoras de Insulina/citología , Masculino , Ratones , Proteína Neuronal del Síndrome de Wiskott-Aldrich/genéticaRESUMEN
Overly rapid correction of chronic hyponatremia can cause osmotic demyelination syndrome (ODS). Minocycline protects ODS associated with overly rapid correction of chronic hyponatremia with hypertonic saline infusion in rats. In clinical practice, inadvertent rapid correction frequently occurs due to water diuresis, when vasopressin action suddenly ceases. In addition, vasopressin receptor antagonists have been applied to treat hyponatremia. Here the susceptibility to and pathology of ODS were evaluated using rat models developed to represent rapid correction of chronic hyponatremia in the clinical setting. The protective effect of minocycline against ODS was assessed. Chronic hyponatremia was rapidly corrected by 1 (T1) or 10 mg/kg (T10) of tolvaptan, removal of desmopressin infusion pumps (RP), or administration of hypertonic saline. The severity of neurological impairment in the T1 group was significantly milder than in other groups and brain hemorrhage was found only in the T10 and desmopressin infusion removal groups. Minocycline inhibited demyelination in the T1 group. Further, immunohistochemistry showed loss of aquaporin-4 (AQP4) in astrocytes before demyelination developed. Interestingly, serum AQP4 levels were associated with neurological impairments. Thus, minocycline can prevent ODS caused by overly rapid correction of hyponatremia due to water diuresis associated with vasopressin action suppression. Increased serum AQP4 levels may be a predictive marker for ODS.
Asunto(s)
Antagonistas de los Receptores de Hormonas Antidiuréticas/toxicidad , Benzazepinas/toxicidad , Enfermedades Desmielinizantes/prevención & control , Diuresis/efectos de los fármacos , Hiponatremia/terapia , Minociclina/farmacología , Fármacos Neuroprotectores/farmacología , Solución Salina Hipertónica/toxicidad , Terapéutica/efectos adversos , Animales , Acuaporina 4/sangre , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Astrocitos/patología , Conducta Animal/efectos de los fármacos , Biomarcadores/sangre , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Encéfalo/fisiopatología , Quimiocinas/genética , Quimiocinas/metabolismo , Citocinas/genética , Citocinas/metabolismo , Citoprotección , Desamino Arginina Vasopresina , Enfermedades Desmielinizantes/sangre , Enfermedades Desmielinizantes/inducido químicamente , Enfermedades Desmielinizantes/genética , Enfermedades Desmielinizantes/patología , Enfermedades Desmielinizantes/psicología , Modelos Animales de Enfermedad , Hiponatremia/sangre , Hiponatremia/inducido químicamente , Hiponatremia/fisiopatología , Hemorragias Intracraneales/inducido químicamente , Hemorragias Intracraneales/prevención & control , Masculino , Metaloproteinasas de la Matriz/genética , Metaloproteinasas de la Matriz/metabolismo , Ósmosis , Ratas Sprague-Dawley , Solución Salina Hipertónica/administración & dosificación , Sodio/sangre , Factores de Tiempo , Tolvaptán , Equilibrio Hidroelectrolítico/efectos de los fármacosRESUMEN
The immunoglobulin heavy chain binding protein (BiP) is an endoplasmic reticulum (ER) chaperone, which binds to newly synthesized secretory and transmembrane proteins to facilitate protein folding. BiP mRNA is expressed in the arginine vasopressin (AVP) neurons in the supraoptic nucleus of wild-type mice even in basal conditions, and the expression levels increase in response to dehydration. These data suggest that AVP neurons are subjected to ER stress. Familial neurohypophysial diabetes insipidus (FNDI) is caused by mutations in the gene locus of AVP. The mutant proteins could accumulate in the ER and possibly increase ER stress in the AVP neurons. We bred mice possessing a mutation causing FNDI, which manifested progressive polyuria, as do the patients with FNDI. Electron microscopic analyses demonstrated that aggregates accumulated in the ER of AVP neurons in FNDI mice. Despite polyuria, which could potentially induce dehydration, AVP mRNA expression was decreased in the supraoptic nucleus, and the AVP mRNA poly(A) tail length was shortened in FNDI mice compared with wild-type mice. Incubation of hypothalamic explants of wild-type mice with ER stressors caused shortening of the poly(A) tail length of AVP mRNA, accompanied by decreases in the expression. These data revealed a mechanism by which ER stress decreases poly(A) tail length of AVP mRNA, and this reduces the load of unfolded proteins that form the aggregates in ER of the AVP neurons in FNDI mice.
Asunto(s)
Diabetes Insípida Neurogénica/patología , Estrés del Retículo Endoplásmico/fisiología , Neuronas/patología , Vasopresinas/metabolismo , Animales , Diabetes Insípida Neurogénica/genética , Diabetes Insípida Neurogénica/metabolismo , Modelos Animales de Enfermedad , Retículo Endoplásmico/genética , Retículo Endoplásmico/metabolismo , Retículo Endoplásmico/patología , Humanos , Hipotálamo/metabolismo , Hipotálamo/patología , Ratones , Pliegue de Proteína , ARN Mensajero/genética , Vasopresinas/genéticaRESUMEN
Central diabetes insipidus (CDI) is caused by deficiency of arginine vasopressin, an antidiuretic hormone. Patients with CDI manifest polyuria which is usually compensated for by increases in water intake. However, some patients are not able to sense thirst due to the destruction of osmoreceptors in the hypothalamus. These adipsic CDI patients are easily dehydrated and the consequent dehydration could be life-threatening. The objective of this study was to investigate the prognosis of adipsic CDI patients. We have reviewed 149 patients with CDI in three hospitals using databases of the electronic medical recording systems, and examined whether adipsia could affect the morbidity and mortality in CDI patients with multivariable analyses. Twenty-three patients with CDI were adipsic while the remaining 126 patients were non-adipsic. The multivariate analyses showed that the incidence of serious infections which required hospitalization was significantly higher in the adipsic CDI patients compared to that in non-adipsic CDI patients (p <0.001). A total of 6 patients with CDI died during the follow-up (median duration; 60 months, range 1 to 132 months). Four of them were adipsic, three of whom died of infection. The statistical analyses revealed that the risk of death in adipsic CDI patients was significantly higher than in non-adipsic patients (p =0.007). It is thus suggested that adipsic CDI patients were susceptible to serious infections which could be the causes of death.
Asunto(s)
Deshidratación/etiología , Diabetes Insípida Neurogénica/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Deshidratación/mortalidad , Diabetes Insípida Neurogénica/complicaciones , Femenino , Humanos , Infecciones/mortalidad , Masculino , Persona de Mediana Edad , Morbilidad , SedRESUMEN
Although pituitary function is often impaired in pituitary apoplexy, the development of thyrotoxicosis is rare. We describe an unusual case of hypopituitarism due to pituitary apoplexy coexisting with transient hyperthyroidism. A 74-year-old woman presented with severe fatigue, palpitation, appetite loss, hypotension, and hyponatremia. Endocrine studies showed hyperthyroidism and anterior pituitary hormone deficiencies. A magnetic resonance imaging suggested recent-onset pituitary apoplexy in a pituitary tumor, although the patient had no apoplectic symptoms such as headache and visual disturbance. Thyrotoxicosis and adrenal insufficiency worsened her general condition. Glucocorticoid supplementation improved her clinical symptoms and hyponatremia. Serum anti-thyrotropin receptor and thyroid-stimulating antibody titers were negative, and her thyroid function was spontaneously normalized without antithyroid medication, suggesting painless thyroiditis. Thereafter, her thyroid function decreased because of central hypothyroidism and 75 µg of levothyroxine was needed to maintain thyroid function at the euthyroid stage. The pituitary mass was surgically removed and an old hematoma was detected in the specimen. Considering that painless thyroiditis develops as a result of an autoimmune process, an immune rebound mechanism due to adrenal insufficiency probably caused painless thyroiditis. Although the most common type of thyroid disorder in pituitary apoplexy is central hypothyroidism, thyrotoxicosis caused by painless thyroiditis should be considered even if the patient has pituitary deficiencies. Because thyrotoxicosis with adrenal insufficiency poses a high risk for a life-threatening adrenal crisis, prompt diagnosis and treatment are critical.