RESUMEN
Once central diabetes insipidus (CDI) has been diagnosed, every effort should be made to reveal its underlying cause. Autoimmune CDI should be considered in the differential diagnosis of idiopathic CDI and also of mass lesions of the sella region. An autoimmune etiology of CDI was first suggested in 1983 by the detection of autoantibodies to hypothalamic vasopressin-producing cells (AVPcAb) in adults and also in children with the disease, using the indirect immunofluorescence test. The major autoantigen for autoimmune CDI has now been recognized as rabphilin-3A, a protein of secretory vesicles of the neurohypophyseal system. The detection of autoantibodies to rabphilin-3A by Western blotting or of AVPcAb provides strong evidence for the diagnosis of autoimmune CDI. Autoimmune CDI is recognized mostly in patients who had also been diagnosed with endocrine autoimmune disorders. The radiological and morphological correlate with autoimmune DI is lymphocytic infundibuloneurohypophysitis (LINH) as detected by magnetic resonance imaging and biopsies that show massive infiltration of the posterior pituitary and the infundibulum with lymphocytes and some plasma cells, and fibrosis in the later stages of the disease. LINH may be associated with lymphocytic anterior hypophysitis. Both may either appear spontaneously or on treatment with immune checkpoint inhibitors.
Asunto(s)
Enfermedades Autoinmunes , Hipofisitis Autoinmune , Diabetes Insípida Neurogénica , Diabetes Insípida , Diabetes Mellitus Tipo 1 , Neurohipófisis , Adulto , Hipofisitis Autoinmune/diagnóstico , Niño , Diabetes Insípida Neurogénica/diagnóstico , Diabetes Insípida Neurogénica/etiología , Humanos , Imagen por Resonancia MagnéticaRESUMEN
11-Keto-ß-Boswellic acid (KBA) has been shown to prevent infiltration of lymphocytes into pancreatic islets and appearance of peri-insular apoptotic cells in an animal model of autoimmune diabetes caused by injection of Multiple Low Doses of Streptozotocin (MLD-STZ), which is a chemical compound belonging to the class of nitrososureas. The aim of this work was to study whether or not KBA can also prevent/attenuate infiltration of lymphocytes into pancreatic islets and appearance of peri-insular apoptotic cells in an animal model of autoimmune diabetes caused by genetic dysfunction resembling human type 1 diabetes in several important features. Four weeks old female NOD mice received daily i.p. injections of 7.5 mg/kg of KBA over a period of 3 weeks. Compared to 4 weeks old animals there was significant infiltration of lymphocytes (CD3) into pancreatic islets and appearance of peri-insular apoptotic cells in the period between 4 and 7 weeks. During this time plasma glucose dropped significantly and body weight did not increase. As far as pro-inflammatory cytokines are concerned, except a small increase of IFN-γ, there was no change in the blood. In mice that had been treated with KBA between 4 and 7 weeks after birth no significant infiltration of lymphocytes into pancreatic islets and appearance of peri-insular apoptotic cells was observed, when compared to 4 weeks old mice. Moreover, there was no drop of blood glucose and the animals gained body weight. It is concluded that - similar to the model of MLD-STZ-diabetes - also in the NOD mouse model KBA is able to attenuate or even prevent development of insulitis, suggesting that KBA protects islets from autoimmune reaction regardless whether the signal is provided by a chemical compound or by genetic dysfunction. Whether this also holds for human type 1 diabetes remains to be established.
Asunto(s)
Complejo CD3/metabolismo , Islotes Pancreáticos/inmunología , Linfocitos/metabolismo , Triterpenos/farmacología , Animales , Animales Recién Nacidos , Apoptosis/efectos de los fármacos , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Citocinas/sangre , Femenino , Hiperglucemia/sangre , Hiperglucemia/patología , Mediadores de Inflamación/metabolismo , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/patología , Linfocitos/efectos de los fármacos , Ratones Endogámicos NOD , Ratones Obesos , Triterpenos/químicaRESUMEN
OBJECTIVE: We related organ-specific autoantibodies, including diabetes-associated autoantibodies (DAAs) and non-DAAs to systemic cytokines/chemokines in type 1 and type 2 diabetes. RESEARCH DESIGN AND METHODS: From the European Action LADA (latent autoimmune diabetes in adults) cohort, patients with adult-onset type 1 diabetes (n = 80, of whom 50 had LADA and 30 had classic type 1 diabetes) and type 2 diabetes (n = 626) were analyzed for DAAs (GAD antibody [GADA], IA-2 antigen, islet cell antibody, and zinc transporter T8), non-DAAs (transglutaminase, thyroid peroxide autoantibodies, parietal cell antibodies), and 10 immune mediator concentrations (measured by LUMINEX). RESULTS: Type 1 diabetes patients (whether having classic type 1 diabetes or LADA), apart from their clinical phenotype, could not be distinguished by either autoantibodies (both DAAs and non-DAAs) or immune mediators. In type 1 diabetes, most immune mediators (9 of 10) were negatively correlated with DAA titers. Type 2 diabetes patients, who by definition were without DAAs, had fewer non-DAAs (P < 0.0005), but had higher levels of proinflammatory immune mediators, especially compared with patients with type 1 diabetes who had high GADA titers (interleukin [IL]-6 [P < 0.001], soluble E-selectin [P < 0.01], and IL-1 receptor antagonist [P = 0.052], for trend). CONCLUSIONS: Patients with type 1 diabetes had more DAAs and non-DAAs than did those with type 2 diabetes, whereas the frequency and nature of these autoantibodies was broadly similar in classic type 1 diabetes and LADA. Systemic immune mediator levels, in the main, were negatively correlated with DAA titers, and, for some, were higher in patients with type 2 diabetes, especially when compared with patients who had high GADA titers. Differences in the clinical classification of diabetes are associated with graded differences in adaptive and innate immune reactivity.
Asunto(s)
Autoanticuerpos/inmunología , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 2/inmunología , Diabetes Autoinmune Latente del Adulto/inmunología , Adulto , Anciano , Proteínas de Transporte de Catión/inmunología , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Selectina E/metabolismo , Femenino , Glutamato Descarboxilasa/inmunología , Humanos , Proteína Antagonista del Receptor de Interleucina 1/inmunología , Interleucina-6/inmunología , Yoduro Peroxidasa/inmunología , Diabetes Autoinmune Latente del Adulto/metabolismo , Masculino , Persona de Mediana Edad , Células Parietales Gástricas/inmunología , Fenotipo , Transglutaminasas/inmunología , Transportador 8 de ZincRESUMEN
BACKGROUND: In the pathogenesis of limbic encephalitis other promoting factors besides the pure existence of autoantibodies are increasingly discussed to play a significant role. This is to our knowledge the first described patient in whom the presence of autoantibodies precedes the manifestation of limbic encephalitis for many years. CASE PRESENTATION: At the age of 38 years, in the serum of a patient with polyendocrine autoimmunity high titers of cytoplasmic islet cell antibodies and of anti-glutamate decarboxylase (GAD) 65 antibodies were observed as an incidential finding, GAD67 antibodies were negative at that time. After a latency of 18 years, she manifested with refractory temporal lobe epilepsy most likely due to autoimmune limbic encephalitis. After epilepsy onset, the patient underwent magnetic resonance imaging (MRI), electroencephalography, cerebrospinal fluid (CSF), serum and neuropsychological investigations during a follow-up period of 8 years. A pharmacoresistent epilepsy with seizure onset from the right temporal lobe and declarative memory deficits were observed affecting primarily the recall of verbal informations. MRI showed a slightly increased signal in the right amygdala without progression. GAD antibodies could be detected in serum (titre 1: 1000) and CSF (titre 1:1) by immunofluorescence. Both, GAD65 and GAD67 antibodies were observed in cell-based assays. CONCLUSIONS: It can be assumed that in addition to a pre-existing systemic T-cell response associated with the longstanding polyendocrine autoimmunity, a delayed intrathecal autoimmunity developed leading to limbic encephalitis. This change might be reflected by the development of GAD67 antibodies in our patient. Besides the contribution of this case report to a better understandig of the pathomechanisms for the development of central nervous system (CNS) autoimmunity, it also has a clinical impact as early treatment of GAD antibody-associated CNS disorders has a better prognosis. Therefore, vigilance for symptoms indicating GAD antibody-associated CNS autoimmunity is mandatory in patients with GAD antibody-associated endocrine dysfunction.
Asunto(s)
Anticuerpos/sangre , Enfermedades Autoinmunes/inmunología , Glutamato Descarboxilasa/inmunología , Encefalitis Límbica/inmunología , Adulto , Epilepsia del Lóbulo Temporal/etiología , Femenino , HumanosAsunto(s)
Diabetes Mellitus Tipo 2/terapia , Educación del Paciente como Asunto , Anciano , Terapia Combinada , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/diagnóstico , Medicina Basada en la Evidencia , Medicina General , Alemania , Humanos , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/uso terapéutico , Medicina InternaRESUMEN
AIMS: It is of interest to understand how insulin therapy currently evolves in clinical practice, in the years after starting insulin in people with type 2 diabetes. We aimed to describe this evolution prospectively over 4 years, to assist health care planning. METHODS: People who had started any insulin were identified from 12 countries on three continents. Baseline, then yearly follow-up, data were extracted from clinical records over 4 years. RESULTS: Of the 2999 eligible people, 2272 were followed over 4 years. When starting insulin, mean (SD) duration of diabetes was 10.6 (7.8) years, HbA1c 9.5 (2.0)% (80 [22]mmol/mol) and BMI 29.3 (6.3)kg/m(2). Initial insulin therapy was basal 52%, premix 23%, mealtime+basal 14%, mealtime 8% and other 3%; at 4 years, 30%, 25%, 33%, 2% and 5%, respectively, with 5% not on insulin. Insulin dose was 20.2U/day at the start and 45.8U/day at year 4. There were 1258 people (55%) on their original regimen at 4 years, and this percentage differed according to baseline insulin regimen. HbA1c change was -2.0 (2.2)% (-22 [24]mmol/mol) and was similar by final insulin regimen. Hypoglycaemia prevalence was <20% in years 1-4. Body weight change was mostly in year 1, and was very variable, mean +2.7 (7.5)kg at year 4. CONCLUSION: Different insulin regimens were started in people with differing characteristics, and they evolved differently; insulin dose, hypoglycaemia and body weight change were diverse and largely independent of regimen.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/epidemiología , Hipoglucemia/epidemiología , Hipoglucemiantes/administración & dosificación , Insulina/administración & dosificación , Adulto , Anciano , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Diabetes Mellitus Tipo 2/sangre , Esquema de Medicación , Femenino , Estudios de Seguimiento , Hemoglobina Glucada/análisis , Humanos , Hipoglucemia/sangre , Hipoglucemia/inducido químicamente , Hipoglucemiantes/efectos adversos , Insulina/efectos adversos , Masculino , Persona de Mediana Edad , Planificación de Atención al Paciente/tendencias , Estudios Retrospectivos , Factores de TiempoRESUMEN
Progressive loss of pancreatic ß-cell mass is a crucial feature of type 2 diabetes mellitus. As ß-cells express very low amounts of the antioxidant enzymes catalase and glutathione peroxidase (GPx), they appear to be particularly vulnerable to oxidative damage in the pathogenesis of diabetes. Here, we investigated the pancreatic expression pattern and regulation of selenoprotein P (Sepp1), which may serve as an additional antioxidant enzyme inside and outside of cells. Sepp1 was detected in rodent pancreas by immunofluorescence and real-time RT-PCR. Regulation of Sepp1 biosynthesis in INS-1 rat insulinoma cells was investigated by real-time RT-PCR, luciferase gene reporter assay, and immunoblotting. Sepp1 and Gpx1 gene expressions in rat pancreas were 58 and 22% respectively of the liver values. Pancreatic Sepp1 expression was restricted to the endocrine tissue, with Sepp1 being present in the α- and ß-cells of mouse islets. In INS-1 insulinoma cells, Sepp1 expression was stimulated by the selenium compound sodium selenate and diminished in the presence of high glucose (16.7 vs 5â mM) concentrations. Sepp1 mRNA stability was also lowered at 16.7â mM glucose. Moreover, Sepp1 mRNA levels were decreased in isolated murine islets cultured in high-glucose (22 âmM) medium compared with normal glucose (5.5 âmM) medium. Pancreatic Sepp1 expression was elevated upon treatment of mice with the ß-cell toxin streptozotocin. This study shows that pancreatic islets express relatively high levels of Sepp1 that may fulfill a function in antioxidant protection of ß-cells. Downregulation of Sepp1 expression by high glucose might thus contribute to glucotoxicity in ß-cells.
Asunto(s)
Islotes Pancreáticos/metabolismo , Selenoproteína P/metabolismo , Animales , Western Blotting , Línea Celular Tumoral , Regulación hacia Abajo , Técnica del Anticuerpo Fluorescente , Genes Reporteros , Glucosa/administración & dosificación , Ratones , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Selenoproteína P/biosíntesis , Selenoproteína P/genética , Estreptozocina/farmacologíaAsunto(s)
Anticonceptivos Orales/uso terapéutico , Dexametasona/farmacología , Hidrocortisona/orina , Adolescente , Adulto , Anticonceptivos Orales/sangre , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Etinilestradiol/uso terapéutico , Reacciones Falso Positivas , Femenino , Humanos , Hidrocortisona/sangre , Persona de Mediana Edad , Estudios Retrospectivos , Adulto JovenRESUMEN
OBJECTIVE: Specific autoantibodies characterize type 1 diabetes in childhood but are also found in adult-onset diabetes, even when initially non-insulin requiring, e.g., with latent autoimmune diabetes (LADA). We aimed to characterize adult-onset autoimmune diabetes. RESEARCH DESIGN AND METHODS: We consecutively studied 6,156 European diabetic patients attending clinics within 5 years of diagnosis (age range, 30-70 years) examined cross-sectionally clinically and for GAD antibodies (GADA) and antibodies to insulinoma-associated antigen-2 (IA-2A) and zinc-transporter 8 (ZnT8A). RESULTS: Of 6,156 patients, 541 (8.8%) had GADA and only 57 (0.9%) IA-2A or ZnT8A alone. More autoantibody-positive than autoantibody-negative patients were younger, leaner, on insulin (49.5 vs. 13.2%), and female (P < 0.0001 for each), though LADA patients (9.7% of total) did not show categorically distinct clinical features from autoantibody-negative type 2 diabetes. Similarly, more GADA patients with high (>200 World Health Organization IU) (n = 403) compared with low (n = 138) titer were female, lean, and insulin treated (54.6 vs. 39.7%) (P < 0.02 for each). Autoantibody-positive patients usually had GADA (541 of 598; 90.5%) and had LADA more often than type 1 autoimmune diabetes (odds ratio 3.3). CONCLUSIONS: Adult-onset autoimmune diabetes emerges as a prevalent form of autoimmune diabetes. Our results indicate that adult-onset autoimmune diabetes in Europe encompasses type 1 diabetes and LADA in the same broad clinical and autoantibody-positive spectrum. At diagnosis, patients with adult-onset autoimmune diabetes are usually non-insulin requiring and clinically indistinguishable from patients with type 2 diabetes, though they tend to be younger and leaner. Only with screening for autoantibodies, especially GADA, can they be identified with certainty.
Asunto(s)
Diabetes Mellitus Tipo 1/epidemiología , Adulto , Anciano , Autoanticuerpos/inmunología , Proteínas de Transporte de Catión/inmunología , Estudios Transversales , Diabetes Mellitus Tipo 1/inmunología , Europa (Continente)/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Transportador 8 de ZincRESUMEN
Natural killer (NK) cells belong to the innate immune system. Besides their role in antitumor immunity, NK cells also regulate the activity of other cells of the immune system, including dendritic cells, macrophages, and T cells, and may, therefore, be involved in autoimmune processes. The aim of the present study was to clarify the role of NK cells within this context. Using two mouse models for type 1 diabetes mellitus, a new subset of NK cells with regulatory function was identified. These cells were generated from conventional NK cells by incubation with IL-18 and are characterized by the expression of the surface markers CD117 (also known as c-Kit, stem cell factor receptor) and programmed death (PD)-ligand 1. In vitro analyses demonstrated a direct lysis activity of IL-18-stimulated NK cells against activated insulin-specific CD8(+) T cells in a PD-1/PD-ligand 1-dependent manner. Flow cytometry analyses revealed a large increase of splenic and lymphatic NK1.1(+)/c-Kit(+) NK cells in nonobese diabetic mice at 8 wk of age, the time point of acceleration of adaptive cytotoxic immunity. Adoptive transfer of unstimulated and IL-18-stimulated NK cells into streptozotocin-treated mice led to a delayed diabetes development and partial disease prevention in the group treated with IL-18-stimulated NK cells. Consistent with these data, mild diabetes was associated with increased numbers of NK1.1(+)/c-Kit(+) NK cells within the islets. Our results demonstrate a direct link between innate and adaptive immunity in autoimmunity with newly identified immunoregulatory NK cells displaying a potential role as immunosuppressors.
Asunto(s)
Autoinmunidad/inmunología , Antígenos CD8/metabolismo , Células Asesinas Naturales/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Animales , Apoptosis/fisiología , Células Cultivadas , Diabetes Mellitus Experimental/inmunología , Diabetes Mellitus Experimental/metabolismo , Citometría de Flujo , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Microscopía Fluorescente , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
We asked whether plasma concentrations of endothelin-1 (ET-1) or adrenomedullin (ADM) are altered by different activity states of the renin-angiotensin-aldosterone system (RAAS). Levels of ET-1 and ADM were studied in patients with primary aldosteronism (n = 15), essential hypertension (n = 15), and adrenal insufficiency (n = 7). Effects of fludrocortisone, dexamethasone, or spironolactone treatment on ET-1 and ADM levels were also analyzed. Plasma ET-1 and ADM concentrations did not differ significantly between the patient groups. After fludrocortisone, dexamethasone, or spironolactone treatment, both ET-1 and ADM did not change significantly. The data support the hypothesis that the RAAS is not directly linked with the ET-1/ADM system.
Asunto(s)
Adrenomedulina/sangre , Antiinflamatorios/uso terapéutico , Dexametasona/uso terapéutico , Endotelina-1/sangre , Fludrocortisona/uso terapéutico , Hipertensión/tratamiento farmacológico , Espironolactona/uso terapéutico , Insuficiencia Suprarrenal/tratamiento farmacológico , Adulto , Biomarcadores/sangre , Diuréticos/uso terapéutico , Femenino , Humanos , Hiperaldosteronismo/tratamiento farmacológico , Hipertensión/sangre , Hipertensión/fisiopatología , Masculino , Persona de Mediana Edad , Sistema Renina-Angiotensina/efectos de los fármacosRESUMEN
CONTEXT: Hashimoto's thyroiditis (HT) is a common autoimmune disease leading to thyroid destruction due to lymphocytic infiltration. Only rare data are available regarding the recognition of specific cellular antigens, e.g. of thyroperoxidase (TPO) and thyroglobulin (Tg). OBJECTIVE: The aim of this study was to quantify and characterize TPO- and Tg-epitope-specific CD8-positive T cells of HT patients. DESIGN: Six different human leukocyte antigen (HLA)-A2 restricted, TPO- or Tg-specific tetramers were synthesized and used for measuring CD8-positive T cells in HT patients and controls. RESULTS: The frequency of peripheral TPO- and Tg-specific CD8-positive T cells was significantly higher in HLA-A2-positive HT patients (2.8 ± 9.5%) compared with HLA-A2-negative HT patients (0.5 ± 0.7%), HLA-A2-positive nonautoimmune goiter patients (0.2 ± 0.4%), and HLA-A2-positive healthy controls (0.1 ± 0.2%). The frequency of Tg-specific T cells (3.0%) was very similar to those of TPO-specific CD8-positive T cells (2.9%). Subgroup analyses revealed a steady increase of the number of epitope-specific CD8-positive T cells from 0.6 ± 1.0% at initial diagnosis up to 9.4 ± 18.3% in patients with long-lasting disease. Analyses of the number of thyroid-infiltrating cells as well as the cytotoxic capacity revealed a similar picture for TPO- and Tg-specific T cells. CONCLUSION: We here report for the first time that both antigens, TPO and Tg, are recognized by CD8-positive T cells and are involved in the thyroid destruction process leading to clinical disease manifestation.
Asunto(s)
Citotoxicidad Celular Dependiente de Anticuerpos , Autoanticuerpos/análisis , Enfermedad de Hashimoto/inmunología , Inmunidad Celular , Yoduro Peroxidasa/antagonistas & inhibidores , Proteínas de Unión a Hierro/antagonistas & inhibidores , Tiroglobulina/antagonistas & inhibidores , Glándula Tiroides/inmunología , Adulto , Anciano , Especificidad de Anticuerpos , Autoanticuerpos/química , Autoantígenos/química , Biopsia con Aguja Fina , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/patología , Epítopos/análisis , Epítopos/química , Femenino , Bocio/inmunología , Bocio/metabolismo , Bocio/patología , Antígeno HLA-A2/metabolismo , Enfermedad de Hashimoto/metabolismo , Enfermedad de Hashimoto/patología , Humanos , Yoduro Peroxidasa/química , Proteínas de Unión a Hierro/química , Masculino , Persona de Mediana Edad , Tiroglobulina/química , Glándula Tiroides/patología , Adulto JovenRESUMEN
Several studies have reported a positive relationship of the body fat mass and bone density. However, it is not clear whether adipocyte-derived signaling molecules directly act on osteoblasts or osteoclasts. Therefore, we investigated the effect of fat cell-secreted factors on the proliferation and differentiation of preosteoblasts and the molecular mechanisms involved. This stimulation led to an increased proliferation of MC3T3-E1 and primary preosteoblastic cells (2.8-fold and 1.5-fold, respectively; p<0.0001), which could be reduced with inhibitors of protein tyrosine kinases, FGFR1 and PI3K. Concordantly, we found human adipocytes to secrete bFGF and bFGF to mimic the effect of adipocyte-secreted factors. The ratio of OPG/RANKL secretion in primary human preosteoblasts increased 9-fold (mRNA and protein) when stimulated with adipocyte-secreted factors. Moreover, osteoblasts which were prestimulated with adipocyte-secreted factors inhibited the formation of osteoclasts. In conclusion, human adipocytes secrete factors that directly act on preosteoblasts and alter their crosstalk with osteoclasts. These in vitro findings reflect the higher bone mass in obese people and attribute it to effects of adipocyte-secreted factors on bone formation.
Asunto(s)
Adipocitos/metabolismo , Osteoblastos/citología , Osteoclastos/citología , Osteoprotegerina/metabolismo , Ligando RANK/metabolismo , Animales , Diferenciación Celular , Proliferación Celular , Células Cultivadas , Medios de Cultivo Condicionados , Ensayo de Inmunoadsorción Enzimática , Humanos , Ratones , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteogénesis/fisiología , Osteoprotegerina/genética , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/farmacología , Ligando RANK/genética , ARN Mensajero/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/metabolismoRESUMEN
The Wnt-signaling pathway regulates ß-cell functions. It is not known how the expression of endogenous Wnt-signaling molecules is regulated in ß-cells. Therefore, we investigated the effect of antidiabetic drugs and glucose on the expression of Wnt-signaling molecules in ß-cells. Primary islets were isolated and cultured. The expression of Wnt-signaling molecules (Wnt-4, Wnt-10b, Frizzled-4, LRP5, TCF7L2) and TNFα was analyzed by semiquantitative PCR and Western blotting. Transient transfections were carried out and proliferation assays of INS-1 ß-cells performed using [(3)H]thymidine uptake and BrdU ELISA. Insulin secretion was quantified. A knockdown (siRNA) of Wnt-4 in ß-cells was carried out. Exendin-4 significantly increased the expression of Wnt-4 in ß-cells on the mRNA level (2.8-fold) and the protein level (3-fold) (P < 0.001). The effect was dose dependent, with strongest stimulation at 10 nM, and it was maintained after long-term stimulation over 4 wk. Addition of exd-(9-39), a GLP-1 receptor antagonist, abolished the effect of exendin-4. Treatment with glucose, insulin, or other antidiabetic drugs had no effect on the expression of any of the examined Wnt-signaling molecules. Functionally, Wnt-4 antagonized the activation of canonical Wnt-signaling in ß-cells. Wnt-4 had no effect on glucose-stimulated insulin secretion or insulin gene expression. Knocking down Wnt-4 decreased ß-cell proliferation to 45% of controls (P < 0.05). In addition, Wnt-4 and exendin-4 treatment decreased the expression of TNFaα mRNA in primary ß-cells. These data demonstrate that stimulation with exendin-4 increases the expression of Wnt-4 in ß-cells. Wnt-4 modulates canonical Wnt signaling and acts as regulator of ß-cell proliferation and inflammatory cytokine release. This suggests a novel mechanism through which GLP-1 can regulate ß-cell proliferation.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Células Secretoras de Insulina/efectos de los fármacos , Péptidos/farmacología , Ponzoñas/farmacología , Proteína Wnt4/genética , Animales , Células Cultivadas , Evaluación Preclínica de Medicamentos , Exenatida , Regulación de la Expresión Génica/efectos de los fármacos , Receptor del Péptido 1 Similar al Glucagón , Glucosa/farmacología , Hipoglucemiantes/farmacología , Insulina/genética , Insulina/metabolismo , Secreción de Insulina , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/fisiología , Metformina/farmacología , Ratones , Ratones Endogámicos C57BL , ARN Interferente Pequeño/farmacología , Receptores de Glucagón/antagonistas & inhibidores , Receptores de Glucagón/metabolismo , Receptores de Glucagón/fisiología , Rosiglitazona , Tiazolidinedionas/farmacología , Tolbutamida/farmacología , Regulación hacia Arriba/efectos de los fármacos , Proteína Wnt4/antagonistas & inhibidores , Proteína Wnt4/metabolismoRESUMEN
BACKGROUND: Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are complex tumors whose incidence is rising and whose treatment requires precise classification and risk stratification. METHOD: Selective review of the relevant literature, including recently published guidelines. RESULTS: GEP-NENs are initially classified by their degree of histological differentiation and their graded cell proliferation (Ki-67 index). In addition, there are GEP-NEN specific TNM staging protocols. The laboratory assessment includes the measurement of general tumor markers (synaptophysin, chromogranin A) as well as specific ones (hormones). The most important imaging technique for diagnosis is octreotide scintigraphy. The surgical treatment of GEP-NEN is based on oncological resection criteria whose aim is to achieve locally radical resection while preserving as much organ function as possible. Metastases, too, may be amenable to resection. The treatment options for unresectable metastases include radiofrequency ablation and chemoembolization, both of which are palliative methods of reducing tumor volume and hormone production. Other chemotherapeutic and nuclear-medical treatments can be applied depending on the extent of metastatic spread, the proliferation index, and the degree of hormone production by the tumor. CONCLUSION: The accurate diagnosis and appropriate treatment of GEP-NET currently gives most patients with this tumor a good prognosis, as long as it is discovered early. Early GEP-NETs have a favorable prognosis. Further advances in the diagnosis and treatment of this disease may result from structural changes in patient care, including the establishment of NET centers.
Asunto(s)
Neoplasias Gastrointestinales/diagnóstico , Neoplasias Gastrointestinales/terapia , Tumores Neuroendocrinos/diagnóstico , Tumores Neuroendocrinos/terapia , HumanosRESUMEN
OBJECTIVE: Diabetes mellitus type 2 (DM2) is a risk factor for coronary heart disease (CHD). While there is a clear correlation of fasting blood glucose (FBG) and 2 h post-challenge blood glucose values (2h-BG) with microvascular complications, the risk for CHD conferred by glucose dysregulation antecedent to DM2 is less clear. Therefore, we investigated associations of FBG and 2h-BG values with the prevalence of CHD assessed by coronary angiography as the most sensitive diagnostic tool. RESEARCH DESIGN AND METHODS: Coronary angiography was performed in 1394 patients without known DM. Capillary blood glucose was analyzed before and 2 h after an oral glucose tolerance test. Associations between FBG as well as 2h-BG levels and the risk for CHD were assessed by logistic regression analysis. RESULTS: 1064 (75%) of patients were diagnosed with CHD. 204 (15%) were diagnosed with so far unknown DM2, 274 (20%) with isolated impaired fasting glucose (IFG), 188 (13%) with isolated impaired glucose tolerance (IGT) and 282 (20%) with both, IGT and IFG. We found a continuous increase in the risk for CHD with fasting and post-challenge blood glucose values even in the subdiabetic range. This correlation did however not suggest clear cut-off values. The increase in risk for CHD reached statistical significance at FBG levels of > 120 mg/dl (Odds Ratio of 2.7 [1.3-5.6] and 2h-BG levels > 140 mg/dl (141-160 mg/dl OR 1.8 [1.1-2.9], which was however lost after adjusting for age, sex and BMI. CONCLUSIONS: In our study population we found a continuous increased risk for CHD at fasting and 2h-BG levels in the sub-diabetic glucose range, but no clear cut-off values for cardiovascular risk.
Asunto(s)
Glucemia/metabolismo , Estenosis Coronaria/diagnóstico por imagen , Estenosis Coronaria/epidemiología , Hiperglucemia/complicaciones , Anciano , Angiografía Coronaria , Progresión de la Enfermedad , Femenino , Humanos , Hiperglucemia/sangre , Modelos Logísticos , Masculino , Persona de Mediana Edad , Prevalencia , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Cushing's disease rarely appears as a consequence of hereditary disease. However, familial diseases with diminished glucocorticoid feedback are associated with secondary hypercorticotropinism and have been shown to give rise to pituitary adenomas. We here describe the rare case of a 30-year old female patient with congenital adrenal hyperplasia who also showed clinical signs and a typical history of hypercortisolism that was specified as Cushing's disease. After removal of a pituitary microadenoma, serum-cortisol levels fell below normal and the symptoms improved. However, after four years the menstrual cycle was irregular again and ACTH levels were in the upper range of normal. A corticotropin challenge showed a minor cortisol response but a marked increase in 17-hydroxyprogesterone serum concentrations. Genetic analysis revealed a homozygous mutation in exon 7 of the CYP21A2 gene (CTG>TTG, p.V281L). We conclude that a marked ACTH drive was able to override insufficient 21-hydroxylation and even to cause hypercortisolism. Although we describe a rare case, the impairment of the glucocorticoid feedback system in the context of congenital adrenal hyperplasia and other diseases may contribute to the development of secondary hypercorticotropinism as well as corticotropin producing adenomas.