RESUMEN
PURPOSE: Vitamin D and osteoporosis in Graves' disease (GD) have been examined in cross-sectional studies with divergent results. Here, we prospectively studied vitamin D metabolism and bone health in patients with newly diagnosed GD. METHODS: Thirty consecutive patients with de novo overt thyrotoxicosis diagnosed with GD were included. At diagnosis, none of the patients were treated with vitamin D or anti-osteoporotic drugs. All patients were initially treated with antithyroid drugs. Blood samplings were taken at baseline and at 6 weeks, 3, 6, 12 and 24 months after treatment start. Serum levels of 25OHD3, 1,25OH2D3, calcium, parathyroid hormone (PTH), and C-terminal telopeptides of Type I collagen (CTX-I) were analysed. Bone mineral density (BMD) was measured at baseline, and 1 and 2 years after treatment initiation. RESULTS: At diagnosis, patients with GD did not have vitamin D deficiency. There were no significant correlations between levels of 25OHD3 and thyrotoxicosis. Upon treatment of the thyrotoxicosis, serum calcium fell transiently, and PTH and 1,25OH2D3 increased. 25OHD3 fell within the normal range and stabilised at 6 months. CTX-I fell over 12 months, BMD increased significantly up to 2 years, p = 0.002, < 0.001 and 0.005 in the spine, left total hip and left femoral neck, respectively. CONCLUSIONS: The present data underline that thyrotoxicosis has a negative impact on bone health and demonstrate fine-tuned dynamics in bone and vitamin D metabolism. Upon treatment, bone health improved over a follow-up period of 24 months despite rising PTH. Increased conversion of 25OHD3 to 1,25OH2D3 occurs during treatment of GD.
Asunto(s)
Enfermedad de Graves , Tirotoxicosis , Deficiencia de Vitamina D , Humanos , Vitamina D , Estudios Prospectivos , Calcio , Estudios Transversales , Hormona Paratiroidea , Densidad Ósea , Calcifediol , Vitaminas/uso terapéutico , Enfermedad de Graves/complicaciones , Enfermedad de Graves/tratamiento farmacológico , Enfermedad de Graves/metabolismo , Deficiencia de Vitamina D/complicacionesRESUMEN
PURPOSE: Serum thyroglobulin levels are often elevated in Graves' disease (GD) and in most cases decrease during treatment. Its relation to Graves' orbitopathy (GO) has not been clarified. Previously, a risk of GO has been linked to smoking, TSH receptor stimulation, high TSH-receptor antibodies (TRAb), low thyroid peroxidase and thyroglobulin antibodies (TPOAb, TgAb). METHODS: We examined Tg levels in 30 consecutive patients with GD were given drug therapy (methimazole + thyroxine) for up to 24 months. GO was identified by clinical signs and symptoms. 17 patients had GO, 11 of whom had it at diagnosis while 6 developed GO during treatment. During the study, 5 subjects were referred to radioiodine treatment, 3 to surgery. The remaining 22 subjects (GO n = 12, non-GO n = 10) completed the drug regimen. RESULTS: At diagnosis, Tg levels in GO patients (n = 11) were higher (84, 30-555 µg/L, median, range) than in non-GO patients (n = 19) (38, 3.5-287 µg/L), p = 0.042. Adding the 6 subjects who developed eye symptoms during treatment to the GO group (n = 17), yielded p = 0.001 vs. non-GO (n = 13). TRAb tended to be higher, while TPOAb and TgAb tended to be lower in the GO group. For the 22 patients who completed the drug regimen, Tg levels were higher in GO (n = 12) vs. non-GO (n = 10), p = 0.004, whereas TRAb levels did not differ. CONCLUSION: The data may suggest that evaluation of thyroglobulin levels in GD could contribute to identify patients at increased risk of developing GO. Possibly, thyroidal release of Tg in GD reflects a disturbance that also impacts retroorbital tissues.
Asunto(s)
Enfermedad de Graves/sangre , Enfermedad de Graves/patología , Oftalmopatía de Graves/sangre , Oftalmopatía de Graves/patología , Órbita/patología , Tiroglobulina/sangre , Adulto , Anciano , Antitiroideos/uso terapéutico , Biomarcadores , Femenino , Enfermedad de Graves/tratamiento farmacológico , Oftalmopatía de Graves/tratamiento farmacológico , Humanos , Radioisótopos de Yodo/uso terapéutico , Masculino , Metimazol/uso terapéutico , Persona de Mediana Edad , Pronóstico , Hormonas Tiroideas/sangre , Tiroxina/uso terapéutico , Fumar TabacoRESUMEN
AIMS: After initiation of treatment in Type 1 diabetes, a period with lower insulin requirement often follows, reflecting increased insulin sensitivity and improved insulin secretion. We explored if efficiency of proinsulin processing is associated with the remission phenomenon. METHODS: Seventy-eight patients with new-onset Type 1 diabetes were followed prospectively for 3 years. Daily insulin dosage, HbA(1c) , plasma glucose, proinsulin, C-peptide, glucagon concentrations and islet antibodies were determined at diagnosis and after 3, 6, 9, 12, 18, 24, 30 and 36 months. We studied remission, defined as an insulin dose ≤ 0.3 U kg(-1) 24 h(-1) and HbA(1c) within the normal range, in relation to the above-mentioned variables. RESULTS: A rise and subsequent decline in plasma proinsulin and C-peptide concentrations was observed. Forty-five per cent of the patients experienced remission at one or more times, characterized by higher proinsulin and C-peptide levels, and lower proinsulin/C-peptide ratios, indicating more efficient proinsulin processing, compared with those not in remission. Non-remission also tended to be associated with higher glucagon values. Patients entering remission were more often men, had higher BMI at diagnosis, but did not differ at baseline with respect to islet antibody titres compared with patients with no remission. CONCLUSIONS: Remissions after diagnosis of Type 1 diabetes were associated with lower proinsulin/C-peptide ratios, suggesting more efficient proinsulin processing, and tended to have lower glucagon release than non-remissions. This indicates that, in remission, the residual islets maintain a secretion of insulin and glucagon of benefit for control of hepatic glucose production.
Asunto(s)
Péptido C/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Glucagón/metabolismo , Hemoglobina Glucada/metabolismo , Proinsulina/metabolismo , Adolescente , Adulto , Biomarcadores/metabolismo , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/terapia , Progresión de la Enfermedad , Ayuno , Femenino , Humanos , Resistencia a la Insulina , Masculino , Estudios Prospectivos , Valores de Referencia , Inducción de Remisión , Adulto JovenRESUMEN
BACKGROUND: Obesity is associated with increased risk of cardiovascular disease. We investigated vasoreactivity in conduit and resistance arteries in morbidly obese subjects, and the effect of weight loss after gastric bypass surgery. METHODS: A total of 19 obese subjects (body mass index (BMI): 43.8+/-3.1 kg m(-2), 75% female, mean age 41 years) were investigated before surgery and after 1 and 12 months of surgery. Nineteen non-obese controls matched for age and gender were examined. Vasoreactivity was evaluated by ultrasound to measure flow-mediated dilation (FMD, evaluating a conduit vessel) and pulse-wave analysis with terbutaline provocation (change in reflectance index (RI), evaluating resistance vessels). RESULTS: Before surgery, the obese showed a low change in RI (18+/-12 vs 37+/-15% in controls, P=0.0001), but not significantly regarding FMD (7.9+/-6.4 vs 8.9+/-5.4% in controls). Surgery resulted in a weight loss of 9% at 1 month and 30% at 1 year. Change in RI markedly improved to 36+/-12% at 1 month (P=0.0001 vs baseline) and further to 44+/-11% at 1 year (P=0.014 vs 1 month). FMD did not change significantly. Heart rate and brachial artery diameter were reduced, with no significant change in blood pressure. The improvement in resistance vessel vasodilation, estimated as change in RI, was not correlated to changes in weight or measures of glucose and lipid metabolism. CONCLUSIONS: Obese patients showed impaired vasoreactivity in resistance arteries that was normalized already 1 month after gastric bypass surgery. The basis for this remarkable outcome, not significantly related to changes in body weight and metabolic variables, remains to be clarified.
Asunto(s)
Arteria Braquial/fisiopatología , Derivación Gástrica/métodos , Obesidad Mórbida/fisiopatología , Resistencia Vascular/fisiología , Adulto , Índice de Masa Corporal , Arteria Braquial/diagnóstico por imagen , Arteria Braquial/cirugía , Femenino , Humanos , Masculino , Obesidad Mórbida/diagnóstico por imagen , Obesidad Mórbida/cirugía , Pronóstico , Resultado del Tratamiento , UltrasonografíaRESUMEN
Cultured human lymphocytes and rat hepatoma cells were labeled with [32P]orthophosphate and the insulin receptor subunits identified by immunoprecipitation and sodium dodecyl sulfate-gel electrophoreses. In both cell types the 95,000-dalton (beta) subunit of the insulin receptor was selectively phosphorylated. Phosphorylation was specifically stimulated by insulin in a dose-dependent fashion after 1 and 15 minutes of hormone treatment, whereas human growth hormone was without effect. This phosphorylation may be a very early event in insulin action.
Asunto(s)
Insulina/farmacología , Receptor de Insulina/metabolismo , Animales , Células Cultivadas , Hormona del Crecimiento/farmacología , Humanos , Neoplasias Hepáticas Experimentales/metabolismo , Linfocitos , Sustancias Macromoleculares , Peso Molecular , Fosforilación , RatasRESUMEN
Cushing's syndrome during pregnancy is rare, and rather than being of pituitary origin most patients exhibit ACTH-independent adrenal hypercortisolism. In some cases the syndrome has spontaneously resolved post partum, suggesting the presence of a pregnancy-associated stimulatory factor(s). We describe a case with aberrant adrenal LH/hCG receptors in a large adrenal tumor as a possible explanation for cortisol hypersecretion and tumor growth in Cushing s syndrome during pregnancy. A 27-yr-old woman presented with hypertension and diabetes mellitus in early pregnancy. Investigations revealed hypercortisolemia, suppressed ACTH-levels, and a 6.4- cm right adrenal tumor. The tumor was successfully removed by laparoscopy at 26th week of pregnancy. Hypercortisolism and hypertension resolved post-operatively. The tumor displayed higher LH/hCG receptor mRNA and protein positivity than adjacent normal adrenal tissue as examined by in situ hybridization and immunocytochemistry. High physiological levels of hCG, in conjunction with aberrant adrenal LH/hCG receptor overexpression, may have contributed to the development of Cushing's syndrome in pregnancy.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales/metabolismo , Hormona Adrenocorticotrópica/metabolismo , Síndrome de Cushing/metabolismo , Complicaciones Neoplásicas del Embarazo , Receptores de HL/metabolismo , Neoplasias de las Glándulas Suprarrenales/complicaciones , Neoplasias de las Glándulas Suprarrenales/diagnóstico , Adulto , Síndrome de Cushing/complicaciones , Síndrome de Cushing/diagnóstico , Femenino , Humanos , Técnicas para Inmunoenzimas , Embarazo , ARN Mensajero/metabolismo , Receptores de HL/genética , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
OBJECTIVE: The marked weight loss induced by Roux-en-Y gastric bypass (RYGBP) for morbid obesity is still incompletely understood. It has been suggested that, besides the restriction imposed by the surgical procedure, alterations in gut regulatory peptides signaling the brain might contribute. The aim of this study was to measure the putative satiety peptides peptide YY (PYY), glucagon-like peptide-1 (GLP-1), pancreatic polypeptide (PP) and pro-neurotensin (pro-NT) in response to fasting and feeding. DESIGN: The study is a cross-sectional study. After a prolonged overnight 14 h fast, a standardized mixed meal (574 kcal) was provided. Blood samples for peptide measurements were obtained before and after the meal. SUBJECTS: Forty subjects (20 males and females) were included; 10 morbidly obese; (mean age 41+/-7 years; mean BMI 44+/-3 kg/m(2)), 10 operated with RYGBP (age 45+/-5 years; BMI 35+/-6 kg/m(2)), 10 aged-matched lean (age 44+/-5 years; BMI 24+/-3 kg/m(2)) and 10 young lean subjects (age 26+/-2 years; BMI 23+/-2 kg/m(2)). MEASUREMENTS: Plasma concentrations of PYY, GLP-1, PP and pro-NT were obtained. RESULTS: PYY levels increased more in the RYGBP group than in the other groups after the test meal. GLP-1 levels rose in the RYGBP patients, with a small increase seen in the age-matched lean group. PP concentrations increased similarly in all groups postprandially. Pro-NT levels were highest in surgical patients, with no meal effect. CONCLUSION: RYGBP subjects displayed exaggerated PYY and GLP-1 responses to a standardized meal and demonstrated higher pro-NT levels both pre- and postprandially. The findings indicate that possibly the alterations in gut peptide secretion may promote weight loss after gastric bypass surgery.
Asunto(s)
Cirugía Bariátrica , Péptido 1 Similar al Glucagón/metabolismo , Neurotensina/metabolismo , Obesidad Mórbida/metabolismo , Polipéptido Pancreático/metabolismo , Péptido YY/metabolismo , Precursores de Proteínas/metabolismo , Adulto , Estudios Transversales , Ingestión de Alimentos/fisiología , Ayuno/fisiología , Femenino , Humanos , Masculino , Obesidad Mórbida/cirugía , Periodo Posprandial , Estudios Prospectivos , Respuesta de Saciedad/fisiología , Pérdida de Peso/fisiologíaRESUMEN
BACKGROUND: Recent developments of magnetic resonance imaging (MRI) and spectroscopy have made it possible to quantify lipid deposited in different tissues. To what extent an improvement of glucose tolerance shortly after Roux-en-Y gastric bypass surgery (RYGBP) is reflected in lipid levels in liver and skeletal muscle, markers of insulin resistance, has not been clarified. METHODS: Whole-body MRI and MR spectroscopy (MRS) of liver and muscle and measurements of biochemical markers of glucose and lipid metabolism were performed at baseline and 1, 6, and 12 months following surgery in seven morbidly obese women. Volumes of adipose tissue depots and liver and muscle lipids were assessed from the MRI/MRS data. RESULTS: At 1 month postoperatively, body mass index and visceral and subcutaneous adipose tissues were reduced by 9%, 26%, and 10%, respectively, whereas no reductions in intrahepatocellular or skeletal intramyocellular lipid concentrations were found. Free fatty acid and beta-hydroxybutyrate levels were elevated two- and sixfold, respectively; glucose and insulin levels were lowered, indicating increased insulin sensitivity. Further weight loss up to 1 year was associated with reductions in all investigated lipid depots investigated, with the exception of the intramyocellular compartment. CONCLUSION: RYGBP causes rapid lipid mobilization from visceral and subcutaneous adipose depots and enhanced free fatty acid flux to the liver. An exceptional disconnection between liver fat and insulin sensitivity occurs in the early dynamic phase after surgery. However, in the late phase, the energy restriction imposed by the surgical procedure also reduces the liver lipids, but not the intramyocellular lipids.
Asunto(s)
Resistencia a la Insulina/fisiología , Movilización Lipídica/fisiología , Imagen por Resonancia Magnética , Espectroscopía de Resonancia Magnética , Obesidad Mórbida/metabolismo , Obesidad Mórbida/cirugía , Adiposidad/fisiología , Adulto , Femenino , Estudios de Seguimiento , Derivación Gástrica , Humanos , Hígado/metabolismo , Persona de Mediana Edad , Músculo Esquelético/metabolismo , Adulto JovenRESUMEN
In autoimmune gastritis antibodies against a membrane-bound parietal cell antigen of previously unknown function are present in the sera of patients. In this study, a vesicular membrane preparation of porcine gastric mucosa cells was found to be a potent antigenic source. This preparation blocked greater than 90% of antibody binding to a lysate of gastric mucosa cells. The membrane fraction contained H+,K+-ATPase (EC 3.6.1.36) as the major protein, which in sodium dodecyl sulfate-polyacrylamide gel electrophoresis migrated with a weight of 92 kD. After reduction and alkylation, this component was resolved into two bands of similar staining intensity (92 and 88 kD). Immunoblotting analysis showed that sera of patients recognized antigen with pattern identical to the major protein of the vesicular membranes. Protein A-Sepharose beads preincubated with immunoglobulins of five individual patient (but not control) sera were all found to reduce both the H+,K+-ATPase activity and the amount of parietal cell antigen of a preparation of vesicular membranes solubilized in n-octylglucoside. Taken together, the results of this study indicate that the major parietal cell antigen is identical to the acid-producing enzyme, H+,K+-ATPase, of the parietal cell.
Asunto(s)
Adenosina Trifosfatasas/inmunología , Anemia Perniciosa/inmunología , Autoantígenos/inmunología , Enfermedades Autoinmunes/inmunología , Gastritis/inmunología , Mucosa Gástrica/citología , Mucosa Gástrica/inmunología , ATPasa Intercambiadora de Hidrógeno-Potásio , Humanos , Técnicas de Inmunoadsorción , Peso MolecularRESUMEN
Autoimmune polyendocrine syndrome type I (APS I) and idiopathic Addison's disease are both disorders with adrenal insufficiency but with differences in genetic background, clinical presentation, and extent of extraadrenal manifestations. In this study the major adrenal autoantigen identified with sera from patients with APS I was characterized by analyses using indirect immunofluorescence, Western blots of adrenal subcellular fractions and of recombinant proteins, immunoprecipitations of [35S]methionine-labeled lysates of a human steroid-producing cell line, and studies of enzymatic activity. Sera from patients with APS I, identifying cells in adrenal glands and testes involved in steroid synthesis, reacted in Western blots with a 53-kD antigen, which comigrated with the cytochrome P450 cholesterol side chain cleavage enzyme (SCC). The sera also immunoprecipitated this protein from lysates of radiolabeled adrenal cells. The enzymatic activity of SCC was inhibited by the APS I sera but not by control sera. Sera from patients with idiopathic Addison's disease did not react with the SCC. The results show that the autoimmune responses towards adrenal tissue in patients suffering from APS I and Addison's disease are remarkably selective and suggest that a determination of the antigen involved in a patient with autoimmune adrenal insufficiency will have diagnostic as well as prognostic implications.
Asunto(s)
Enfermedad de Addison/inmunología , Glándulas Suprarrenales/inmunología , Autoantígenos/sangre , Sistema Enzimático del Citocromo P-450/inmunología , Poliendocrinopatías Autoinmunes/inmunología , Enfermedad de Addison/enzimología , Adolescente , Glándulas Suprarrenales/citología , Adulto , Animales , Western Blotting , Células Cultivadas , Niño , Enzima de Desdoblamiento de la Cadena Lateral del Colesterol/inmunología , Femenino , Técnica del Anticuerpo Fluorescente , Humanos , Masculino , Poliendocrinopatías Autoinmunes/enzimología , Pruebas de Precipitina , Ratas , Esteroide 21-Hidroxilasa/inmunologíaRESUMEN
Antibodies against the insulin receptor (Anti-R), which are found in the serum of type B patients with the syndrome of insulin resistance and acanthosis nigricans, inhibit the binding of insulin to its receptor and mimic the actions of insulin when studied acutely in vitro. After prolonged exposure of 3T3-L1 cells to Anti-R, the insulinomimetic activity is lost, and the cells show a marked decrease in their maximal response to insulin (antibody-induced desensitization), thus providing a model for the insulin resistance seen in vivo. This study explores in detail the mechanism and specificity of desensitization in 3T3-L1 cells.Desensitization, like the insulinomimetic activity of Anti-R, requires bivalence. Monovalent preparations of Anti-R inhibit insulin binding and shift the insulin biological dose-response curve to the right, but do not decrease the maximal insulin response. The affinity of monovalent Anti-R is less than that of the native antibody. Cross-linking of monovalent Anti-R reconstitutes its insulinomimetic activity and partially reconstitutes desensitization. Desensitized cells are resistant to the insulinomimetic actions of concanavalin A, which interacts with the insulin receptor, but are not desensitized to spermine and vitamin K(5), insulinomimetic agents that are thought to act independently of the insulin receptor. Glucose, pyruvate, or certain hexoses are required in the incubation media for desensitization to occur. Although Anti-R is taken up into cells and degraded by lysosomes, chloroquine, cycloheximide, colchicine, and cytochalasin E have little influence on the induction of or recovery from antibody-induced desensitization. These data suggest that desensitization is not merely due to the inhibition of insulin binding, but is a complex process involving a decreased ability of the receptor to generate a biological response.
Asunto(s)
Anticuerpos , Resistencia a la Insulina , Receptor de Insulina/inmunología , Animales , Línea Celular , Fibroblastos/inmunología , Glucosa/metabolismo , Fragmentos Fab de Inmunoglobulinas , Insulina/metabolismo , Antagonistas de Insulina , Especificidad por SustratoRESUMEN
Plasmids containing cDNA for the rat 67- and 65-kD isoforms of glutamate decarboxylase (GAD-67 and GAD-65) were expressed in COS-cells, and lysates of [35S]methionine-labeled cells were used for immunoprecipitations. Sera from 38 patients with type 1 (insulin-dependent) diabetes mellitus, which precipitated a 64-kD antigen from rat islets, reacted with recombinant GAD-65 in relation to their anti-64-kD titers. The eight strongest sera also precipitated recombinant GAD-67, suggesting that certain epitopes are common to both isoforms. Subsequently, [35S]methionine-labeled GAD-65 was purified from COS cell lysates and employed in a binding assay with 50 sera of patients with recent onset of type 1 diabetes mellitus. 38 sera (76%) precipitated labeled GAD-65 with titers that correlated with islet cell antibodies (ICA), determined in a standard immunofluorescence assay. 2 sera were GAD positive but ICA negative, 4 were positive only for ICA, and 6 were negative for both GAD and ICA, as were the sera of 20 controls. The data illustrate that antibodies against GAD-65 are present in a majority of patients with type 1 diabetes mellitus and that autoantibodies against other islet cell antigens also exist. The radioligand-binding assay, which is convenient and sensitive for detecting GAD antibodies, will facilitate the screening of individuals with autoimmune islet cell disease.
Asunto(s)
Autoanticuerpos/sangre , Diabetes Mellitus Tipo 1/enzimología , Diabetes Mellitus Tipo 1/inmunología , Glutamato Descarboxilasa/sangre , Isoenzimas/sangre , Adolescente , Adulto , Anciano , Animales , Línea Celular , Niño , Chlorocebus aethiops , Clonación Molecular , ADN/genética , Diabetes Mellitus Tipo 1/sangre , Electroforesis en Gel de Poliacrilamida , Femenino , Glutamato Descarboxilasa/genética , Glutamato Descarboxilasa/inmunología , Humanos , Immunoblotting , Islotes Pancreáticos/inmunología , Isoenzimas/genética , Isoenzimas/inmunología , Riñón , Masculino , Persona de Mediana Edad , Peso Molecular , Ratas , Valores de Referencia , TransfecciónRESUMEN
Glutamic acid decarboxylase (GAD) is a major islet cell autoantigen in insulin-dependent diabetes mellitus (IDDM), and autoantibodies are found in high frequencies in patients with recent-onset IDDM, stiff-man syndrome (SMS), and autoimmune polyendocrine syndrome type I (APS I). Antigens in autoimmune disorders are often enzymes, and autoantibody binding frequently inhibit their activity. In this study, we examined the reactivity of anti-GAD-containing sera from 7 patients with IDDM, 4 patients with SMS, and 5 patients with APS I. All sera immunoprecipitated GAD from [35S]methionine-labeled rat islet lysates and the sera from patients with SMS and APS I, but none of the IDDM patients' sera, identified the GAD protein in Western blots. Two of four SMS patients' sera and 5 of 5 APS I patients' sera, in contrast to 0 of 7 IDDM patients' sera, inhibited the enzymatic activity of GAD. When the various sera were tested with the GAD65 and GAD67 isoforms, produced separately by transient expression in COS cells, the enzymatic activity of GAD65 was inhibited by sera from patients with SMS and APS I, whereas no effect on the GAD67 activity was observed. Taken together, the results demonstrate that the GAD autoantibodies in these three disorders display marked differences in epitope recognition and indicate that, during the development of the diseases, the autoantigen is being presented to the immune system through separate pathogenetic mechanisms.
Asunto(s)
Autoanticuerpos/sangre , Diabetes Mellitus Tipo 1/inmunología , Epítopos/análisis , Glutamato Descarboxilasa/inmunología , Poliendocrinopatías Autoinmunes/inmunología , Síndrome de la Persona Rígida/inmunología , Adolescente , Adulto , Anciano , Animales , Western Blotting , Línea Celular , Niño , Diabetes Mellitus Tipo 1/sangre , Femenino , Glutamato Descarboxilasa/aislamiento & purificación , Glutamato Descarboxilasa/metabolismo , Humanos , Islotes Pancreáticos/enzimología , Cinética , Masculino , Persona de Mediana Edad , Poliendocrinopatías Autoinmunes/sangre , Ratas , Ratas Endogámicas WF , Valores de Referencia , Síndrome de la Persona Rígida/sangre , TransfecciónRESUMEN
This study examined the effect of various extracellular glucose concentrations on the expression of a previously described 64,000-Mr islet cell autoantigen associated with insulin-dependent diabetes mellitus. The protein was precipitated from patient serums incubated with Triton X-100 lysates of [35S]methionine-labeled rat pancreatic islets that had been cultured in 5, 11, or 28 mM glucose for 6 h or 3 days. In both types of experiment, 28 mM glucose was the most efficient stimulator of 64,000-Mr autoantigen production. In contrast, the class I antigens of the major histocompatibility complex, precipitated by a rabbit polyclonal antiserum, were not influenced by differences in glucose concentrations. Our data indicate that expression of islet cell antigens may be increased during the course of hyperglycemia and suggest that the functional activity of islet cells influences their antigenicity.
Asunto(s)
Autoantígenos/aislamiento & purificación , Glucosa/farmacología , Islotes Pancreáticos/inmunología , Animales , Células Cultivadas , Electroforesis en Gel de Poliacrilamida , Islotes Pancreáticos/efectos de los fármacos , Masculino , Peso Molecular , Ratas , Ratas Endogámicas WFRESUMEN
The effect of age on ICA and thyrogastric antibodies at diagnosis of IDDM was evaluated in 633 consecutively diagnosed Swedish diabetic patients aged 15-34 yr and in 282 volunteers of the same age. ICAs were present in 61% (383 of 633) of the patients and in 2% (5 of 282) of control subjects. When the initial classification was considered, ICAs were detected in 69% (327 of 473) of patients with IDDM, 23% (19 of 83) of those with NIDDM, 50% (36 of 72) of those with unclassifiable diabetes, and 20% (1 of 5) of those with secondary diabetes. The frequency of ICA fell significantly (P less than 0.001) with age in IDDM patients from 77% (104/135) in those 15-19 yr old to 52% (50 of 96) in 30- to 34-yr-old IDDM patients. The low frequency of ICA in 30- to 34-yr-old IDDM patients was confined to men (42%, 28 of 66). The frequency of gastric (H+, K(+)-ATPase) antibodies was significantly (P less than 0.05) higher in IDDM patients (10%, 47 of 449) than in patients with NIDDM (3%, 3 of 80) and unclassifiable diabetes (4%, 3 of 72). In conclusion, the frequency of ICA at the diagnosis of IDDM in young adult subjects decreases with increasing age, particularly in men. The frequent finding of ICA in patients considered to have NIDDM or unclassifiable diabetes indicates that misclassification of diabetes is frequent in young adult patients recently diagnosed with diabetes.
Asunto(s)
Autoanticuerpos/sangre , Diabetes Mellitus/inmunología , Islotes Pancreáticos/inmunología , Estómago/inmunología , Glándula Tiroides/inmunología , Adolescente , Adulto , Factores de Edad , Análisis de Varianza , Diabetes Mellitus/epidemiología , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Incidencia , Masculino , Suecia/epidemiologíaRESUMEN
We examined the influence of two K(ATP) channel openers, diazoxide and an analog (NNC 55-0118), on experimental beta-cell damage induced by streptozotocin (STZ; 0.5 mmol/l). Rat pancreatic islets were exposed to diazoxide or NNC 55-0118 for 30 min and were further incubated for 30 min after the addition of STZ. The islets were then washed and cultured for 24 h. Islets exposed to STZ alone showed extensive morphological damage, reduced glucose oxidation, low insulin content, and severely impaired glucose-stimulated insulin secretion and proinsulin biosynthesis. Islets treated with STZ in the presence of the channel openers (0.03-0.30 mmol/l) showed dose-dependent preservation of the morphology and improved glucose oxidation rates, insulin content, and secretion. NNC 55-0118 was capable of fully counteracting the STZ impairment, whereas diazoxide had a less protective effect. NNC 55-0118 did not counteract STZ-induced depression of islet NAD levels when examined 2 h after STZ exposure, which suggests that the mechanism of action by NNC 55-0118 is not through an inhibition of poly(ADP-ribose) polymerase. The results illustrate that K(ATP) channel openers can protect insulin-producing cells against toxic damage, an effect that may be of use in subjects with ongoing insulitis.
Asunto(s)
Diazóxido/análogos & derivados , Diazóxido/farmacología , Islotes Pancreáticos/efectos de los fármacos , Canales de Potasio/fisiología , Estreptozocina/toxicidad , Animales , Células Cultivadas , Glucosa/metabolismo , Glucólisis/efectos de los fármacos , Insulina/metabolismo , Secreción de Insulina , Islotes Pancreáticos/citología , Islotes Pancreáticos/fisiología , Cinética , Poli(ADP-Ribosa) Polimerasas/metabolismo , Canales de Potasio/agonistas , Proinsulina/biosíntesis , Ratas , Ratas Sprague-Dawley , Estreptozocina/antagonistas & inhibidoresRESUMEN
Twenty islet cell antibody (ICA)-positive patients, aged 19-38 years, with IDDM were randomized at onset to treatment with either diazoxide, a K+ channel opener that inhibits the release of insulin, or placebo for 3 months, in addition to multiple insulin injection therapy. The patients who were given diazoxide displayed higher residual insulin secretion than the placebo group after 1 year (basal C-peptide level, 0.40 +/- 0.04 vs. 0.25 +/- 0.04 [mean +/- SE] nmol/l; P < 0.021) and at an 18-month follow-up (0.37 +/- 0.06 vs. 0.20 +/- 0.01 nmol/l, P < 0.033). Metabolic control did not differ between the two groups. During the course of the study, no differences in islet cell or GAD autoantibodies were detected between the two groups. The results of this study warrant further trials to explore the potential of inducing target cell rest in order to halt the loss of insulin-producing cells during the early course of the disease.
Asunto(s)
Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diazóxido/uso terapéutico , Insulina/metabolismo , Islotes Pancreáticos/metabolismo , Adulto , Autoanticuerpos/sangre , Péptido C/sangre , Péptido C/metabolismo , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/fisiopatología , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Glucagón , Glutamato Descarboxilasa/inmunología , Humanos , Insulina/sangre , Insulina/uso terapéutico , Secreción de Insulina , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/inmunología , Masculino , Placebos , Factores de TiempoRESUMEN
The pancreatic B-cell GLUT2 transporter and glucose metabolism were examined in isolated rat islets subjected to treatments affecting insulin secretion. Diazoxide was used to inhibit, while glipizide or depolarization of the plasma membrane with a high extracellular K(+) concentration were used to stimulate insulin release in short-term experiments. Islet GLUT2 and insulin were determined by quantitative immunohistochemistry and GLUT2 was also determined by Western blot analysis. Islet net glucose uptake and glucose oxidation were measured using radioactively labelled glucose. Exposure of the islets to diazoxide was associated with a marked increase in the B-cell plasma membrane staining for GLUT2 and increased net glucose uptake. Glucose oxidation was not changed, which may reflect a lowered energy requirement. Conversely, islets subjected to a stimulated insulin secretion with glipizide or a high extracellular K(+) concentration showed a reduced staining of the GLUT2 transporter. The net glucose uptake and glucose oxidation were also reduced. In islets exposed to the high K(+) concentration no change in the molecular weight or phosphorylation of GLUT2 was observed but a lesser amount of the transporter was found by Western blot analysis. Thus, GLUT2 and glucose uptake in the pancreatic B-cell are modified by the secretory process, which suggests that changes in the glucose transporter have a functional role in normal B-cell physiology.
Asunto(s)
Diazóxido/farmacología , Glucosa/metabolismo , Hipoglucemiantes/farmacología , Insulina/metabolismo , Islotes Pancreáticos/metabolismo , Proteínas de Transporte de Monosacáridos/metabolismo , Animales , Western Blotting/métodos , Técnicas de Cultivo de Célula , Membrana Celular/metabolismo , Espacio Extracelular/metabolismo , Glipizida/farmacología , Transportador de Glucosa de Tipo 2 , Inmunohistoquímica/métodos , Insulina/análisis , Secreción de Insulina , Islotes Pancreáticos/efectos de los fármacos , Masculino , Proteínas de Transporte de Monosacáridos/análisis , Oxidación-Reducción , Potasio/metabolismo , Ratas , Ratas Sprague-Dawley , Estimulación QuímicaRESUMEN
The optimal thyroid surgery to be performed in patients with Graves' disease and concomitant endocrine ophthalmopathy is a matter of debate. We randomly assigned 44 patients with moderate-severe eye signs in a trial of treatment with subtotal, leaving a small (approximately 2 g) thyroid remnant, or total thyroidectomy. At inclusion, the patients had been treated with antithyroid drugs, and corticosteroids been given to 12 (27%). All received postoperative thyroxine supplementation and were followed for 3 years at regular examinations. The eye disease improved in all cases, and throughout the study, the two groups did not differ with regard to subjective and objective eye symptoms and laboratory findings. At the study start, motility disturbances were present in 8 and 11 of the cases in the subtotal and total resection group and proptosis in 16 and 17, respectively. After 3 years, the corresponding data were 3 and 6 cases with motility defects and 16 and 15 cases with proptosis. Thyrotropin (TSH)-receptor antibody levels gradually fell and became nondetectable in 21 (49%). The surgical complication rate (permanent recurrent laryngeal nerve paresis and permanent hypoparathyroidism) was significantly higher in the total thyroidectomy group. The data indicate that in patients with Graves' disease and active endocrine ophthalmopathy, subtotal thyroidectomy, leaving a small thyroid remnant, will reduce the risk of surgical complications but not the beneficial effect of surgery.
Asunto(s)
Oftalmopatía de Graves/cirugía , Tiroidectomía , Adulto , Anciano , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Trastornos de la Motilidad Ocular/etiología , Receptores de Tirotropina/inmunología , Tiroidectomía/efectos adversos , Tiroidectomía/métodosRESUMEN
OBJECTIVE: To evaluate the inhibitory effects of octreotide and diazoxide on insulin secretion in patients with type 1 diabetes and measurable levels of circulating C-peptide. RESEARCH DESIGN AND METHODS: Diazoxide was given to six patients during a 7-day period (100 mg three times daily), followed by a 3-week washout. Subsequently, octreotide (50 micrograms, three times daily) was administered subcutaneously for 7 days. Pre- and post- prandial blood glucose and serum C-peptide concentrations were measured before medication (control) and on day 7 of each medication period. Glucagon-stimulated C-peptide was determined in the morning before medication and on the day after each treatment period. RESULTS: Diazoxide inhibited glucagon-stimulated C-peptide secretion (mean increment 0.08 nmol/l vs. 0.18 nmol/l, P < 0.05), whereas octreotide had no such effect. Both reduced the pre- and postprandial serum C-peptide concentrations (P < 0.05), octreotide being the more potent in this respect. A reduction in basal and meal-related blood glucose was observed during octreotide treatment, whereas the glucose concentrations tended to be higher during treatment with diazoxide than during the 24-h control period. CONCLUSIONS: The study indicates that the two drugs reduce insulin output by different mechanisms. Diazoxide inhibits hormonal release directly on the beta-cells, whereas octreotide exerts its effect indirectly, presumably by multiple actions on insulin sensitivity and insulin-releasing hormones. The results suggest that each drug is capable of inducing beta-cell rest in type 1 diabetes.