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BACKGROUND: Few reports exist of the long-term management of recurrent and progressive papillary thyroid carcinoma (PTC) with a tyrosine kinase inhibitor for over 5 years. CASE PRESENTATION: A 57-year-old woman was referred to a psychiatric hospital for the treatment of schizophrenia. The patient had been diagnosed with a PTC at the age of 40 and subsequently underwent a left thyroid lobectomy. At 47, completion total thyroidectomy and lymph node dissection were performed and the patient assessed as radioactive iodine refractory postoperatively. External radiation therapy was performed for Rouviere lymph nodes. At 57, neck and mediastinal lymph nodes, and lung metastases had progressed, and the trachea became narrowed by para-tracheal lymph node compression. After 2 weeks of sorafenib therapy on an outpatient basis, the patient was discovered unconsciousness at home and transferred to hospital by ambulance; sorafenib therapy was stopped. The patient was diagnosed with reversible posterior leukoencephalopathy syndrome by brain magnetic resonance imaging. External radiation therapy to the site of the tracheal stenosis in the neck and mediastinum was performed. The patient's mental symptoms worsened, and she was referred to a psychiatric hospital, Kachi Memorial Hospital, in July 2015. In September, the patient's mental state stabilized and in November, after computed tomography revealed rapid disease progression, lenvatinib was commenced at a daily dose of 24 mg. Measurable solid recurrence sites were neck lymph nodes in the pre-laryngeal subcutaneous space, right lobe of the lung, and left adrenal. After 3 months, the tumors shrank in a partial response (PR). Because of several adverse events, occasional dose reductions or discontinuations of lenvatinib were sometimes necessary. Since re-starting lenvatinib, treatment with this for 51 consecutive months was achieved while maintaining a PR. Although a new bone metastasis was noted after 57 months of lenvatinib, treatment was continued for another 9 months. The patient subsequently passed away in June 2021. CONCLUSIONS: The long-term treatment of recurrent PTC with lenvatinib was feasible, with manageable adverse events, for more than 5 years.
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BACKGROUND: Cyclic variation of heart rate (CVHR) associated with sleep-disordered breathing reflects cardiac autonomic responses to apneic/hypoxic stress. However, the association of CVHR with cardiac function is unclear. METHODS: We investigated a total of 181 patients who underwent both 24-hour Holter electrocardiography (ECG) and quantitative gated single-photon emission computed tomography (SPECT) myocardial functional imaging, excluding patients with atrial fibrillation, myocardial infarction, structural heart disease, and implantable devices, from January 2017 to July 2018. The number of CVHR per hour (CVHR index) in sleeping-time Holter ECG was compared with the parameters of left ventricular (LV) systolic and diastolic functions assessed by cardiac SPECT functional imaging, peak filling rate (PFR), first-third mean filling rate (1/3 MFR), and time to peak filling rate (TTPF). RESULTS: In all patients, the CVHR index was not associated with any parameters of cardiac functions. However, in a propensity score-matched subgroup of patients without ischemia (N = 39), the CVHR index was negatively correlated with PFR (r = -0.35, P < .05) and 1/3 MFR (r = -0.37, P < .05) but positively correlated with TTPF (r = 0.43, P < .01) and was not correlated with LV ejection fraction. Multivariate linear regression analysis revealed that high CVHR index was independently associated with LV diastolic dysfunction, even after adjusting for the relative wall thickness and LV mass index assessed by echocardiography. CONCLUSION: These results indicate that the high frequency of CVHR in sleeping time is associated with LV diastolic dysfunction in nonischemic patients, irrespective of LV geometry.
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Emerging evidence suggests that axonal degeneration is a disease mechanism in various neurodegenerative diseases and that the paranodes at the nodes of Ranvier may be the initial site of pathogenesis. We investigated the pathophysiology of the disease process in the central and peripheral nervous systems of a Caspr mutant mouse, shambling (shm), which is affected by disrupted paranodal structures and impaired nerve conduction of myelinated nerves. The shm mice manifest a progressive neurological phenotype as mice age. We found extensive axonal degeneration and a loss of neurons in the central nervous system and peripheral nervous system in aged shm mice. Axonal alteration of myelinated nerves was defined by abnormal distribution and expression of neurofilaments and derangements in the status of phosphorylated and non/de-phosphorylated neurofilaments. Autophagy-related structures were also accumulated in degenerated axons and neurons. In conclusion, our results suggest that disrupted axon-glia interactions at the paranode cause the cytoskeletal alteration in myelinated axons leading to neuronal cell death, and the process involves detrimental autophagy and aging as factors that promote the pathogenesis.
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Envejecimiento/patología , Axones/patología , Axones/fisiología , Degeneración Nerviosa , Fibras Nerviosas Mielínicas/patología , Neuroglía/patología , Neuroglía/fisiología , Neuronas/patología , Potenciales de Acción , Animales , Muerte Celular , Técnicas In Vitro , Ratones Endogámicos C57BL , Ratones Mutantes , Neuronas/fisiología , Nervio Ciático/patología , Nervio Ciático/fisiología , Nervio Ciático/fisiopatologíaRESUMEN
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.
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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
Homozygous glucagon-GFP knock-in mice (Gcggfp/gfp) lack proglucagon derived-peptides including glucagon and GLP-1, and are normoglycemic. We have previously shown that Gcggfp/gfp show improved glucose tolerance with enhanced insulin secretion. Here, we studied glucose and energy metabolism in Gcggfp/gfp mice fed a high-fat diet (HFD). Male Gcggfp/gfp and Gcggfp/+ mice were fed either a normal chow diet (NCD) or an HFD for 15-20 weeks. Regardless of the genotype, mice on an HFD showed glucose intolerance, and Gcggfp/gfp mice on HFD exhibited impaired insulin secretion whereas Gcggfp/+ mice on HFD exhibited increased insulin secretion. A compensatory increase in ß-cell mass was observed in Gcggfp/+mice on HFD, but not in Gcggfp/gfp mice on the same diet. Weight gain was significantly lower in Gcggfp/gfp mice than in Gcggfp/+mice. Oxygen consumption was enhanced in Gcggfp/gfp mice compared to Gcggfp/+ mice on an HFD. HFD feeding significantly increased uncoupling protein 1 mRNA expression in brown adipose and inguinal white adipose tissues of Gcggfp/gfp mice, but not of Gcggfp/+mice. Treatment with the glucagon-like peptide-1 receptor agonist liraglutide (200 mg/kg) improved glucose tolerance in Gcggfp/gfp mice and insulin content in Gcggfp/gfp and Gcggfp/+ mice was similar after liraglutide treatment. Our findings demonstrate that Gcggfp/gfp mice develop diabetes upon HFD-feeding in the absence of proglucagon-derived peptides, although they are resistant to diet-induced obesity.
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Péptido 1 Similar al Glucagón/metabolismo , Intolerancia a la Glucosa/metabolismo , Resistencia a la Insulina/fisiología , Obesidad/metabolismo , Péptidos/metabolismo , Proglucagón/metabolismo , Animales , Dieta Alta en Grasa/métodos , Glucosa/metabolismo , Prueba de Tolerancia a la Glucosa/métodos , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Aumento de Peso/fisiologíaRESUMEN
Animal models with defective glucagon action show hyperplasia of islet α-cells, however, the regulatory mechanisms underlying the proliferation of islet endocrine cells remain largely to be elucidated. The Gcggfp/gfp mice, which are homozygous for glucagon/green fluorescent protein knock-in allele (GCGKO), lack all proglucagon-derived peptides including glucagon and GLP-1. The present study was aimed to characterize pancreatic neuroendocrine tumors (panNETs), which develop in the GCGKO mice. At 15 months of age, macroscopic GFP-positive tumors were identified in the pancreas of all the GCGKO mice, but not in that of the control heterozygous mice. The tumor manifested several features that were consistent with pancreatic neuroendocrine tumors (panNETs), such as organoid structures with trabecular and cribriform patterns, and the expression of chromogranin A and synaptophysin. Dissemination of GFP-positive cells was observed in the liver and lungs in 100% and 95%, respectively, of 15-month-old GCGKO mice. To elucidate the regulatory mechanism for tumor growth, PanNET grafts were transplanted into subrenal capsules in GCGKO and control mice. Ki-67 positive cells were identified in panNET grafts transplanted to GCGKO mice 1 month after transplantation, but not in those to control mice. These results suggest that humoral factors or conditions specific to GCGKO mice, are involved in the proliferation of panNETs. Taken together, GCGKO mice are novel animal model for studying the development, pathogenesis, and metastasis panNETs.
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Péptido 1 Similar al Glucagón/metabolismo , Glucagón/metabolismo , Tumores Neuroendocrinos/metabolismo , Neoplasias Pancreáticas/metabolismo , Animales , Modelos Animales de Enfermedad , Regulación Neoplásica de la Expresión Génica , Glucagón/genética , Péptido 1 Similar al Glucagón/genética , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Inmunohistoquímica , Islotes Pancreáticos/metabolismo , Islotes Pancreáticos/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundario , Ratones , Ratones Noqueados , Ratones Transgénicos , Microscopía Confocal , Tumores Neuroendocrinos/genética , Tumores Neuroendocrinos/patología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Proglucagón/genética , Proglucagón/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Thyroid-stimulating hormone (TSH; thyrotropin) is a glycoprotein secreted from the pituitary gland. Pars distalis-derived TSH (PD-TSH) stimulates the thyroid gland to produce thyroid hormones (THs), whereas pars tuberalis-derived TSH (PT-TSH) acts on the hypothalamus to regulate seasonal physiology and behavior. However, it had not been clear how these two TSHs avoid functional crosstalk. Here, we show that this regulation is mediated by tissue-specific glycosylation. Although PT-TSH is released into the circulation, it does not stimulate the thyroid gland. PD-TSH is known to have sulfated biantennary N-glycans, and sulfated TSH is rapidly metabolized in the liver. In contrast, PT-TSH has sialylated multibranched N-glycans; in the circulation, it forms the macro-TSH complex with immunoglobulin or albumin, resulting in the loss of its bioactivity. Glycosylation is fundamental to a wide range of biological processes. This report demonstrates its involvement in preventing functional crosstalk of signaling molecules in the body.
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Especificidad de Órganos , Procesamiento Proteico-Postraduccional , Tirotropina/metabolismo , Albúminas/metabolismo , Animales , Glicosilación , Inmunoglobulina G/metabolismo , Ratones Endogámicos C57BL , Adenohipófisis/metabolismo , Tirotropina/sangre , Hormona Liberadora de Tirotropina/metabolismoRESUMEN
Attention deficit/hyperactivity disorder (ADHD) has been reported in association with resistance to thyroid hormone, a disease caused by a mutation in the thyroid hormone receptor ß (TRß) gene. TRß is a key protein mediating down-regulation of thyrotropin (TSH) expression by 3,3',5-tri-iodothyronine (T3), an active form of thyroid hormone. Dysregulation of TSH and its receptor (TSHR) is implicated in the pathophysiology of ADHD but the role of TSHR remains elusive. Here, we clarified a novel role for TSHR in emotional and cognitive functions related to monoaminergic nervous systems. TSHR knockout mice showed phenotypes of ADHD such as hyperactivity, impulsiveness, a decrease in sociality and increase in aggression, and an impairment of short-term memory and object recognition memory. Administration of methylphenidate (1, 5 and 10mg/kg) reversed impulsiveness, aggression and object recognition memory impairment. In the knockout mice, monoaminergic changes including decrease in the ratio of 3-methoxy-4-hydroxyphenylglycol/noradrenaline and increase in the ratio of homovanillic acid/dopamine were observed in some brain regions, accompanied by increase in the expression of noradrenaline transporter in the frontal cortex. When TSH was completely suppressed by the supraphysiological administration of T3 to the adult mice, some behavioral and neurological changes in TSHR KO mice were also observed, suggesting that these changes were not due to developmental hypothyroidism induced by the inactivation of TSHR but to the loss of the TSH-TSHR pathway itself. Taken together, the present findings suggest a novel role for TSHR in behavioral and neurological phenotypes of ADHD.
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Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Trastorno por Déficit de Atención con Hiperactividad/genética , Monoaminas Biogénicas/metabolismo , Metilfenidato/uso terapéutico , Sistemas Neurosecretores/metabolismo , Receptores de Tirotropina/genética , Síntomas Afectivos/tratamiento farmacológico , Síntomas Afectivos/genética , Animales , Cognición/efectos de los fármacos , Trastornos del Conocimiento/tratamiento farmacológico , Trastornos del Conocimiento/genética , Emociones/efectos de los fármacos , Masculino , Metilfenidato/farmacología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Resultado del TratamientoRESUMEN
Glucagon, a counterregulatory hormone to insulin, serves as a regulator of glucose homeostasis and acts in response to hypoglycemia. Earlier studies have shown that glucagon administration induces thermogenesis in experimental animal models. However, it is not known whether endogenous glucagon is involved in the regulation of brown adipose tissue (BAT) function. Here we investigated the role of glucagon in cold-induced thermogenesis in male mice deficient in proglucagon-derived peptides (GCGKO mice). Upon exposure to cold, GCGKO mice exhibited a greater decrease in rectal temperature than control mice. The cold exposure-induced increase in oxygen consumption in GCGKO mice was less than that seen in control mice. Moreover, the increase in oxygen consumption after administration of a ß3-adrenergic receptor agonist, CL-316,243, was also lesser in GCGKO than in control mice. Expression of thermogenic genes, including the gene encoding uncoupling protein 1 (Ucp1), was reduced in the BAT of GCGKO mice under ambient as well as cold conditions. Administration of glucagon restored the expression of Ucp1 mRNA in the BAT as well as the expression of the fibroblast growth factor 21 gene (Fgf21) in the liver. Supplementation with glucagon for 2 weeks resulted in higher plasma Fgf21 levels and improved responses to CL-316,243 in GCGKO mice. These results indicated that endogenous glucagon is essential for adaptive thermogenesis and that it regulates BAT function, most likely by increasing hepatic Fgf21 production.
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Tejido Adiposo Pardo/metabolismo , Glucagón/metabolismo , Termogénesis , Adaptación Fisiológica , Animales , Frío , Femenino , Factores de Crecimiento de Fibroblastos/genética , Factores de Crecimiento de Fibroblastos/metabolismo , Canales Iónicos/genética , Canales Iónicos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Oxígeno/metabolismo , Proteína Desacopladora 1RESUMEN
CONTEXT: Hyperthyroidism with the syndrome of inappropriate secretion of TSH (SITSH) occurred by a decrease in hydrocortisone dose after surgery for Cushing's syndrome. This is a novel cause of SITSH. OBJECTIVE: The aim of this study was to describe and discuss 2 cases of SITSH patients that were found after surgery for Cushing's syndrome. We also checked whether SITSH occurred in 7 consecutive patients with Cushing's syndrome after surgery. PATIENTS AND METHODS: A 45-year-old Japanese woman with ACTH-independent Cushing's syndrome and a 37-year-old Japanese man with ACTH-dependent Cushing's syndrome presented SITSH caused by insufficient replacement of hydrocortisone for postoperative adrenal insufficiency. When the dose of hydrocortisone was reduced to less than 20 mg/d within 18 days after surgery, SITSH occurred in both cases. We examined whether the change of the hydrocortisone dose induced the secretion of TSH. Free T3 and TSH were normalized by the hydrocortisone dose increase of 30 mg/d, and these were elevated by the dose decrease of 10 mg/d. We also checked TSH and thyroid hormone levels of the 7 consecutive patients with Cushing's syndrome after surgery. Six (66.6 %) of 9 patients showed SITSH. CONCLUSIONS: This is the first report that insufficient replacement of hydrocortisone after surgery for Cushing's syndrome caused SITSH. Hyperthyroidism by SITSH as well as adrenal insufficiency can contribute to withdrawal symptoms of hydrocortisone replacement. We need to consider the possibility of SITSH for the pathological evaluation of withdrawal syndrome of hydrocortisone replacement.
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Síndrome de Cushing/cirugía , Terapia de Reemplazo de Hormonas , Hidrocortisona/administración & dosificación , Hipertiroidismo/etiología , Complicaciones Posoperatorias , Síndrome de Abstinencia a Sustancias/etiología , Regulación hacia Arriba , Adulto , Síndrome de Cushing/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Monitoreo de Drogas , Femenino , Terapia de Reemplazo de Hormonas/efectos adversos , Humanos , Hidrocortisona/efectos adversos , Hidrocortisona/uso terapéutico , Hipertiroidismo/prevención & control , Masculino , Persona de Mediana Edad , Hipófisis/efectos de los fármacos , Hipófisis/metabolismo , Hipófisis/cirugía , Complicaciones Posoperatorias/prevención & control , Síndrome de Abstinencia a Sustancias/fisiopatología , Síndrome de Abstinencia a Sustancias/prevención & control , Tirotropina/metabolismo , Resultado del TratamientoRESUMEN
Defects in glucagon action can cause hyperplasia of islet α-cells, however, the underlying mechanisms remain largely to be elucidated. Mice homozygous for a glucagon-GFP knock-in allele (Gcg(gfp/gfp) ) completely lack proglucagon-derived peptides and exhibit hyperplasia of GFP-positive α-like cells. Expression of the transcription factor, aristaless-related homeobox (ARX), is also increased in the Gcg(gfp/gfp) pancreas. Here, we sought to elucidate the role of ARX in the hyperplasia of α-like cells through analyses of two Arx mutant alleles (Arx(P355L/Y) and Arx ([330insGCG]7/Y) ) that have different levels of impairment of their function. Expression of Gfp and Arx genes was higher and the size and number of islets increased in the Gcg(gfp/gfp) pancreas compared to and Gcg(gfp/+) pancreas at 2 weeks of age. In male Gcg(gfp/gfp) mice that are hemizygous for the Arx(P355L/Y) mutation that results in a protein with a P355L amino acid substitution, expression of Gfp mRNA in the pancreas was comparable to that in control Gcg(gfp/+)Arx(+/Y) mice. The increases in islet size and number were also reduced in these mice. Immunohistochemical analysis showed that the number of GFP-positive cells was comparable in Gcg(gfp/gfp) Arx(P355L/Y) and Gcg(gfp/+)Arx(+/Y) mice. These results indicate that the hyperplasia is reduced by introduction of an Arx mutation. Arx(P355L/Y) mice appeared to be phenotypically normal; however, Arx ([330insGCG]7/Y) mice that have a mutant ARX protein with expansion of the polyalanine tract had a reduced body size and shortened life span. The number of GFP positive cells was further reduced in the Gcg(gfp/gfp) Arx ([330insGCG]7/Y) mice. Taken together, our findings show that the function of ARX is one of the key modifiers for hyperplasia of islet α-like cells in the absence of proglucagon-derived peptides.
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Proteínas de Homeodominio/metabolismo , Islotes Pancreáticos/metabolismo , Péptidos/metabolismo , Proglucagón/metabolismo , Factores de Transcripción/metabolismo , Animales , Glucemia/metabolismo , Peso Corporal , Femenino , Expresión Génica , Glucagón/genética , Glucagón/metabolismo , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Proteínas de Homeodominio/genética , Hiperplasia , Inmunohistoquímica , Islotes Pancreáticos/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Microscopía Fluorescente , Mutación , Péptidos/genética , Proglucagón/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Transcripción/genéticaRESUMEN
Glucagon and glucagon-like peptide-1 (GLP-1) are produced in pancreatic α-cells and enteroendocrine L-cells, respectively, in a tissue-specific manner from the same precursor, proglucagon, that is encoded by glucagon gene (Gcg), and play critical roles in glucose homeostasis. Here, we studied glucose homeostasis and ß-cell function of Gcg-deficient mice that are homozygous for a Gcg-GFP knock-in allele (Gcg(gfp/gfp)). The Gcg(gfp/gfp) mice displayed improved glucose tolerance and enhanced insulin secretion, as assessed by both oral glucose tolerance test (OGTT) and intraperitoneal glucose tolerance test (IPGTT). Responses of glucose-dependent insulinotropic polypeptide (GIP) to both oral and intraperitoneal glucose loads were unexpectedly enhanced in Gcg(gfp/gfp) mice, and immunohistochemistry localized GIP to pancreatic ß-cells of Gcg(gfp/gfp) mice. Furthermore, secretion of GIP in response to glucose was detected in isolated islets of Gcg(gfp/gfp) mice. Blockade of GIP action in vitro and in vivo by cAMP antagonism and genetic deletion of the GIP receptor, respectively, almost completely abrogated enhanced insulin secretion in Gcg(gfp/gfp) mice. These results indicate that ectopic GIP expression in ß-cells maintains insulin secretion in the absence of proglucagon-derived peptides (PGDPs), revealing a novel compensatory mechanism for sustaining incretin hormone action in islets.
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Polipéptido Inhibidor Gástrico/biosíntesis , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Fragmentos de Péptidos/metabolismo , Proglucagón/metabolismo , Animales , AMP Cíclico/antagonistas & inhibidores , Polipéptido Inhibidor Gástrico/genética , Eliminación de Gen , Técnicas de Sustitución del Gen , Receptor del Péptido 1 Similar al Glucagón , Intolerancia a la Glucosa/genética , Intolerancia a la Glucosa/metabolismo , Prueba de Tolerancia a la Glucosa , Homeostasis/genética , Homeostasis/fisiología , Inmunohistoquímica , Incretinas/metabolismo , Secreción de Insulina , Células Secretoras de Insulina/citología , Masculino , Ratones , Proglucagón/análisis , Receptores de la Hormona Gastrointestinal/genética , Receptores de Glucagón/metabolismoRESUMEN
Resistance to thyroid hormone (RTH) is a syndrome in which the responsiveness of end organs to thyroid hormone (TH) is reduced. Given that the TH-responsive end-organs include pituitary thyrotrophs, almost all patients with RTH manifest unsuppressed thyrotropin (TSH) despite elevated free-T4 and free-T3 levels. This abnormal finding in the thyroid function test is termed "syndrome of inappropriate secretion of TSH" (SITSH) or "central hyperthyroidism". Patients with TSH-secreting pituitary tumors(TSHoma) also manifest SITSH. Thus, the differential diagnosis of RTH vs. TSHoma is sometimes difficult and challenging. In this review article, the etiology of RTH and diagnostic approach for SITSH are explained and an algorithm for differential diagnosis of RTH vs. TSHoma is proposed.
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Hiperpituitarismo/diagnóstico , Síndrome de Resistencia a Hormonas Tiroideas/diagnóstico , Hormonas Tiroideas/metabolismo , Humanos , Hiperpituitarismo/etiología , Hiperpituitarismo/fisiopatología , Hipertiroidismo/etiología , Hipertiroidismo/fisiopatología , Neoplasias Hipofisarias/diagnóstico , Glándula Tiroides/metabolismo , Síndrome de Resistencia a Hormonas Tiroideas/etiología , Síndrome de Resistencia a Hormonas Tiroideas/fisiopatologíaRESUMEN
Proglucagon, which is encoded by the glucagon gene (Gcg), is the precursor of several peptide hormones, including glucagon and glucagon-like peptide 1 (GLP-1). Whereas glucagon stimulates hepatic glycogenolysis and gluconeogenesis, GLP-1 stimulates insulin secretion to lower blood glucose and also supports ß-cell proliferation and protection from apoptotic stimuli. Pregnancy is a strong inducer of change in islet function, however the roles of proglucagon-derived peptides in pregnancy are only partially understood. In the present study, we analyzed fertility and pregnancy-associated changes in homozygous glucagon-green fluorescent protein (gfp) knock-in mice (Gcg(gfp/gfp)), which lack all the peptides derived from proglucagon. Female Gcg(gfp/gfp) mice could deliver and raise Gcg(gfp/gfp) pups to weaning and Gcg(gfp/gfp) pups from Gcg(gfp/gfp) dams were viable and fertile. Pregnancy induced ß-cell proliferation in Gcg(gfp/gfp) mice as well as in control mice. However, serum insulin levels in pregnant Gcg(gfp/gfp) females were lower than those in control pregnant females under ad libitum feeding, and blood glucose levels in pregnant Gcg(gfp/gfp) females were higher after gestational day 12. Gcg(gfp/gfp) females showed a decreased pregnancy rate and smaller litter size. The rate of successful breeding was significantly lower in Gcg(gfp/gfp) females and was not improved by experience of breeding. Taken together, proglucagon-derived peptides are not required for pregnancy-associated ß-cell proliferation, however, are required for regulation of blood glucose levels and normal reproductive capacity. Gcg(gfp/gfp) mice may serve as a novel model to analyze the effect of mild hyperglycemia during late gestational periods.
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Fertilidad , Células Secretoras de Insulina/citología , Fragmentos de Péptidos/metabolismo , Proglucagón/química , Animales , Glucemia/metabolismo , Proliferación Celular , Tamaño de la Célula , Femenino , Técnicas de Sustitución del Gen , Genotipo , Insulina/sangre , Células Secretoras de Insulina/metabolismo , Ratones , Embarazo , Proglucagón/genética , Conducta Sexual AnimalRESUMEN
Calcineurin-nuclear factor of activated T cells signaling controls the differentiation and function of osteoclasts and osteoblasts, and regulator of calcineurin-2 (Rcan2) is a physiological inhibitor of this pathway. Rcan2 expression is regulated by T(3), which also has a central role in skeletal development and bone turnover. To investigate the role of Rcan2 in bone development and maintenance, we characterized Rcan2(-/-) mice and determined its skeletal expression in T(3) receptor (TR) knockout and thyroid-manipulated mice. Rcan2(-/-) mice had normal linear growth but displayed delayed intramembranous ossification, impaired cortical bone formation, and reduced bone mineral accrual during development as well as increased mineralization of adult bone. These abnormalities resulted from an isolated defect in osteoblast function and are similar to skeletal phenotypes of mice lacking the type 2 deiodinase thyroid hormone activating enzyme or with dominant-negative mutations of TRα, the predominant TR isoform in bone. Rcan2 mRNA was expressed in primary osteoclasts and osteoblasts, and its expression in bone was differentially regulated in TRα and TRß knockout and thyroid-manipulated mice. However, in primary osteoblast cultures, T(3) treatment did not affect Rcan2 mRNA expression or nuclear factor of activated T cells c1 expression and phosphorylation. Overall, these studies establish that Rcan2 regulates osteoblast function and its expression in bone is regulated by thyroid status in vivo.
Asunto(s)
Inhibidores de la Calcineurina , Osteoblastos/citología , Proteínas/genética , Proteínas/fisiología , Animales , Fenómenos Biomecánicos , Resorción Ósea , Huesos/metabolismo , Genes Dominantes , Péptidos y Proteínas de Señalización Intracelular , Ratones , Ratones Noqueados , Ratones Transgénicos , Modelos Biológicos , Mutación , Osteoblastos/fisiología , Fosforilación , Isoformas de Proteínas , ARN Mensajero/metabolismo , Linfocitos T/citología , Receptores alfa de Hormona Tiroidea/metabolismo , Receptores beta de Hormona Tiroidea/metabolismo , Microtomografía por Rayos X/métodosRESUMEN
Glucagon is believed to be one of the most important peptides for upregulating blood glucose levels. However, homozygous glucagon-green fluorescent protein (gfp) knock-in mice (Gcg(gfp/gfp): GCGKO) are normoglycemic despite the absence of proglucagon-derived peptides, including glucagon. To characterize metabolism in the GCGKO mice, we analyzed gene expression and metabolome in the liver. The expression of genes encoding rate-limiting enzymes for gluconeogenesis was only marginally altered. On the other hand, genes encoding enzymes involved in conversion of amino acids to metabolites available for the tricarboxylic acid cycle and/or gluconeogenesis showed lower expression in the GCGKO liver. The expression of genes involved in the metabolism of fatty acids and nicotinamide was also altered. Concentrations of the metabolites in the GCGKO liver were altered in manners concordant with alteration in the gene expression patterns, and the plasma concentrations of amino acids were elevated in the GCGKO mice. The insulin concentration in serum and phosphorylation of Akt protein kinase in liver were reduced in GCGKO mice. These results indicated that proglucagon-derived peptides should play important roles in regulating various metabolic pathways, especially that of amino acids. Serum insulin concentration is lowered to compensate the impacts of absent proglucagon-derived peptide on glucose metabolism. On the other hand, impacts on other metabolic pathways are only partially compensated by reduced insulin action.