RESUMEN
OBJECTIVE: Islet immunity and beta cell reserve status were utilized to classify persons with ketoacidosis as the initial manifestation of diabetes. The clinical features of the various diabetes classes were also characterized. DESIGN: Prospective cross sectional study. SETTING: Nelson Mandela Academic Hospital, Mthatha, Eastern Cape Province, South Africa. PATIENTS: Indigenous Black South Africans with ketoacidosis as the initial manifestation of diabetes. INTERVENTIONS: Islet immunity and beta cell reserve were respectively assessed using serum anti-glutamic acid decarboxylase 65 (GAD) antibody and serum C-peptide after 1 mg of intravenous glucagon. OUTCOME MEASURES: Serum anti-GAD 65 antibody > or = 5 units/L and < 5 units/L, respectively defined anti-GAD 65 positive (A+) and negative (A-). Replete (beta+) and deplete (beta-) beta cell reserve were serum C-peptide after glucagon injection of > or = 0.5 ng/mL and < 0.5 ng/mL, respectively. The proportions of patients with A+beta-, A+beta+, A-beta- and A-beta+ and their clinical characteristics were determined. RESULTS: Of the 38 males and 33 females who participated in the study, patients were categorized in various classes: A-beta+, 46.5% (n=33/ 71); A-beta-, 26.8% (n=19/71); A+beta-, 22.5% (n=16/71); and A+beta+, 4.2% (n=3/71). The ages of the various classes were: 41.8 +/- 13.8 years for A-beta+ (n=33); 36.5 +/- 14.6 years for A-beta- (n=19); and 20.6 +/- 7.1 years for the combination of A+beta- with A+beta+ (n=19) (P<.0001, P<.0001 for the combination of A+beta- and A+beta+ vs A-beta+, P=.001 for the combination of A+beta- and A+beta+ vs A-beta-and P=.2 for A-beta- vs A-beta+. The clinical features of type 2 diabetes were most prevalent in A-beta+ class while the A+beta- and A+beta+ groups had the clinical profile of type 1A diabetes. CONCLUSIONS: Most of the indigenous Black South African patients with ketoacidosis as the initial manifestation of diabetes had islet immunity, beta cell reserve status and clinical profiles of type 2 diabetes.
Asunto(s)
Población Negra , Cetoacidosis Diabética/inmunología , Células Secretoras de Insulina/inmunología , Islotes Pancreáticos/inmunología , Acantosis Nigricans/inmunología , Adolescente , Adulto , Anciano , Autoanticuerpos/sangre , Péptido C/sangre , Estudios Transversales , Cetoacidosis Diabética/etnología , Femenino , Glutamato Descarboxilasa/inmunología , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Estudios Seroepidemiológicos , Sudáfrica , Adulto JovenRESUMEN
Acanthosis nigricans (AN) is a cutaneous marker for many underlying states such as endocrine abnormality, obesity, certain drugs, and malignancy. Generalized AN is a rare condition and is commonly seen in adults with an underlying malignancy. The type B insulin resistance syndrome, a rare autoimmune disorder, is caused by the autoantibodies to the insulin receptor. Patients typically present with hyperglycemia but also may present with hypoglycemia. We report a rare case of a 36-year-old man with generalized AN and type B insulin resistance syndrome with hypoglycemia.
Asunto(s)
Acantosis Nigricans/etiología , Hipoglucemia/etiología , Resistencia a la Insulina/inmunología , Acantosis Nigricans/inmunología , Adulto , Enfermedades Autoinmunes/complicaciones , Enfermedades Autoinmunes/inmunología , Humanos , Masculino , SíndromeRESUMEN
Autoantibodies directed against specific epitopes in the insulin receptor are rarely the cause of either recurrent hypoglycemia or a severe form of insulin resistance (type B insulin resistance). Type B insulin resistance occurs more commonly in women of African heritage and is frequently associated with a history of other autoimmune diseases. We present the unusual case of a 61-year-old African American woman with a background of autoimmune hypothyroidism and autoimmune hepatitis who developed type 2 diabetes mellitus and marked facial acanthosis nigricans (AN) over a period of weeks. Despite treatment with multiple oral antidiabetic agents, she rapidly developed severe, recalcitrant hyperglycemia and ketoacidosis, requiring hospitalization and intravenous insulin administration for 4 weeks at rates of up to 180 U/h. Immunologic testing revealed a high titer of anti-insulin receptor autoantibodies of both immunoglobulin G and immunoglobulin A classes. After a recurrence of diabetic ketoacidosis despite aggressive management, the patient was treated with a short course of cyclophosphamide; within 10 weeks, she experienced striking improvement of her hyperglycemia as well as marked regression of the AN lesions. Subsequently, the patient also experienced episodes of fasting hypoglycemia, which resolved with a brief course of glucocorticoids. She has since remained euglycemic with no therapy for 5 years. We have documented, for the first time, regression of AN in temporal association with disappearance of circulating anti-insulin receptor autoantibodies and achievement of euglycemia in a patient with type B insulin resistance.
Asunto(s)
Acantosis Nigricans/inmunología , Autoanticuerpos/sangre , Ciclofosfamida/uso terapéutico , Diabetes Mellitus Tipo 2/inmunología , Inmunosupresores/uso terapéutico , Resistencia a la Insulina/inmunología , Acantosis Nigricans/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Cetoacidosis Diabética/tratamiento farmacológico , Cetoacidosis Diabética/inmunología , Femenino , Humanos , Persona de Mediana EdadRESUMEN
IL-19, IL-20, IL-22, IL-24, and IL-26 are members of the IL-10 family of cytokines that have been shown to be up-regulated in psoriatic skin. Contrary to IL-10, these cytokines signal using receptor complex R1 subunits that are preferentially expressed on cells of epithelial origin; thus, we henceforth refer to them as the IL-20 subfamily cytokines. In this study, we show that primary human keratinocytes (KCs) express receptors for these cytokines and that IL-19, IL-20, IL-22, and IL-24 induce acanthosis in reconstituted human epidermis (RHE) in a dose-dependent manner. These cytokines also induce expression of the psoriasis-associated protein S100A7 and keratin 16 in RHE and cause persistent activation of Stat3 with nuclear localization. IL-22 had the most pronounced effects on KC proliferation and on the differentiation of KCs in RHE, inducing a decrease in the granular cell layer (hypogranulosis). Furthermore, gene expression analysis performed on cultured RHE treated with these cytokines showed that IL-19, IL-20, IL-22, and IL-24 regulate many of these same genes to variable degrees, inducing a gene expression profile consistent with inflammatory responses, wound healing re-epithelialization, and altered differentiation. Many of these genes have also been found to be up-regulated in psoriatic skin, including several chemokines, beta-defensins, S100 family proteins, and kallikreins. These results confirm that IL-20 subfamily cytokines are important regulators of epidermal KC biology with potentially pivotal roles in the immunopathology of psoriasis.
Asunto(s)
Diferenciación Celular/inmunología , Epidermis/inmunología , Interleucinas/farmacología , Psoriasis/inmunología , Acantosis Nigricans/inmunología , Acantosis Nigricans/metabolismo , Acantosis Nigricans/patología , Proteínas de Unión al Calcio/biosíntesis , Proteínas de Unión al Calcio/inmunología , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Citocinas/inmunología , Citocinas/farmacología , Relación Dosis-Respuesta a Droga , Relación Dosis-Respuesta Inmunológica , Epidermis/metabolismo , Epidermis/patología , Humanos , Interleucina-10/inmunología , Interleucinas/inmunología , Queratina-16/biosíntesis , Queratina-16/inmunología , Queratinocitos/inmunología , Queratinocitos/metabolismo , Queratinocitos/patología , Modelos Biológicos , Psoriasis/metabolismo , Psoriasis/patología , Proteína A7 de Unión a Calcio de la Familia S100 , Proteínas S100 , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/inmunologíaAsunto(s)
Acantosis Nigricans/inmunología , Infecciones por VIH/diagnóstico , Infecciones por VIH/inmunología , Seropositividad para VIH/diagnóstico , VIH-1/inmunología , Acantosis Nigricans/complicaciones , Acantosis Nigricans/diagnóstico , Adulto , Femenino , Infecciones por VIH/complicaciones , Seropositividad para VIH/complicaciones , HumanosRESUMEN
The distribution and density of ovine MHC class I and class II antigens in normal, acanthotic and malignantly transformed ovine skin was investigated using monoclonal antibodies and an immunoperoxidase technique. The subjects were sheep that had been exposed to high levels of sunlight for more than 6 years. The expression of MHC class II antigens in the plasma membrane of cells within the normal epidermis was restricted to basally located dendritic and mononuclear cells. Normal keratinocytes did not express MHC class II antigens. However, we observed low levels of intracellular MHC class II expression in both acanthotic and neoplastic keratinocytes. Expression of MHC class I antigens was variable in normal and acanthotic epithelium; it was usually present, but of low intensity in very early ovine squamous cell carcinoma and was increased in small, but morphologically typical, tumors. Tumors originating on the nose, which are more invasive than those on the ear, were found to express significantly less MHC class I (P < 0.05). Thus, an association between tumor invasiveness and low level expression of MHC class I was apparent. This may have diagnostic value and highlights a mechanism by which neoplastic cells may evade immune surveillance by T cells.
Asunto(s)
Acantosis Nigricans/veterinaria , Carcinoma de Células Escamosas/veterinaria , Antígenos de Histocompatibilidad Clase I/biosíntesis , Complejo Mayor de Histocompatibilidad/inmunología , Enfermedades de las Ovejas/inmunología , Neoplasias Cutáneas/veterinaria , Acantosis Nigricans/inmunología , Acantosis Nigricans/patología , Animales , Carcinoma de Células Escamosas/inmunología , Carcinoma de Células Escamosas/patología , Femenino , Antígenos de Histocompatibilidad Clase II/biosíntesis , Técnicas para Inmunoenzimas/veterinaria , Masculino , Invasividad Neoplásica , Ovinos , Enfermedades de las Ovejas/patología , Piel/metabolismo , Piel/patología , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patologíaAsunto(s)
Autoanticuerpos/análisis , Receptor de Insulina/inmunología , Acantosis Nigricans/inmunología , Adolescente , Adulto , Anciano , Enfermedades Autoinmunes/complicaciones , Enfermedades Autoinmunes/inmunología , Unión Competitiva , Femenino , Humanos , Resistencia a la Insulina , Masculino , Persona de Mediana Edad , Pruebas de Precipitina , Receptor de Insulina/análisis , Pruebas de Función de la Tiroides/métodosAsunto(s)
Acantosis Nigricans/etiología , Adenocarcinoma/complicaciones , Anticuerpos Antinucleares/análisis , Neoplasias Pulmonares/complicaciones , Acantosis Nigricans/inmunología , Adenocarcinoma/inmunología , Anciano , Humanos , Neoplasias Pulmonares/inmunología , Activación de Linfocitos , MasculinoRESUMEN
With isoelectric focusing, we examined heterogeneity of autoantibodies to insulin receptors in serums of two patients with insulin-resistant diabetes and one patient with hypoglycemia. Immunoglobulins were prepared by ammonium sulfate precipitation and ion-exchange chromatography with DEAE-Sepharose and subjected to isoelectric focusing for separation into 30 fractions. The fractions were tested for their ability to inhibit 125I-labeled insulin binding to human placental membranes, immunoprecipitate solubilized insulin receptor cross-linked with 125I-insulin, and mimic or inhibit the action of insulin in rat adipocytes. The results varied among the three patients. In the first patient, inhibition of 125I-insulin-binding activity (IBA) and insulin-receptor-precipitating activity (IPA) were distributed almost identically, but the distribution of insulinlike bioactivity (ILBA) was somewhat different. In the second patient, some fractions exhibited potent IBA without IPA, and these fractions inhibited the action of insulin in rat adipocytes. In the third patient, all of the isoelectric fractions showed IBA without IPA and were insulin antagonists. These observations indicate that some patients have antibodies with pure insulin-antagonist properties and provide further evidence that autoantibodies to insulin receptors are polyclonal and recognize different antigenic sites on insulin-receptor molecules. The findings also suggest that the ability of antibodies to elicit ILBA is linked to the ability to immunoprecipitate 125I-insulin-cross-linked and solubilized receptors, whereas antibodies that only inhibit insulin binding behave as insulin antagonists.
Asunto(s)
Anticuerpos Heterófilos/análisis , Autoanticuerpos/análisis , Anticuerpos Insulínicos/análisis , Resistencia a la Insulina , Receptor de Insulina/inmunología , Acantosis Nigricans/inmunología , Tejido Adiposo/inmunología , Adulto , Animales , Femenino , Humanos , Hipoglucemia/inmunología , Inmunoglobulina G/análisis , Focalización Isoeléctrica/métodos , Masculino , Persona de Mediana Edad , Pruebas de Precipitina/métodos , Ratas , Receptor de Insulina/análisisRESUMEN
Plasma insulin clearance was studied in a patient with autoantibodies to the insulin receptor, manifesting persistent hyperinsulinemia associated with alternating hyper- and hypoglycemia. In the postabsorptive period, the plasma glucose level gradually decreased. To prevent the development of hypoglycemia, glucose was infused and the glycemic level was clamped at 50 mg/dl without insulin infusion. The plasma C-peptide level was below the detectable range during the clamp, indicating no appreciable secretion of insulin. The plasma insulin level declined exponentially with a markedly prolonged disappearance rate (half-time: 3.0 h) during the study. These results indicate that hyperinsulinemia in the postabsorptive period in this patient is attributable to the impairment of plasma insulin clearance through receptor-mediated mechanisms, and also confirm that the receptor plays the principal role in plasma insulin removal.
Asunto(s)
Acantosis Nigricans/inmunología , Autoanticuerpos , Insulina/sangre , Receptor de Insulina/inmunología , Acantosis Nigricans/sangre , Glucemia/metabolismo , Técnica de Clampeo de la Glucosa , Humanos , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Receptor de Insulina/metabolismoRESUMEN
Acanthosis nigricans is a skin disorder associated with endocrine abnormalities, autoimmune disease, and systemic malignancies. Insulin resistance is a common accompaniment of the nonmalignant varieties of acanthosis nigricans. A 44-year-old man is described with a functioning metastatic pheochromocytoma, acanthosis nigricans, and insulin-resistant diabetes mellitus. Studies of insulin action showed a low titer of anti-insulin antibodies and a very high titer of antibodies against the insulin receptor. This case documents for the first time insulin resistance due to anti-insulin receptor antibodies in a paraneoplastic variety of acanthosis nigricans.
Asunto(s)
Acantosis Nigricans/inmunología , Neoplasias de las Glándulas Suprarrenales/inmunología , Anticuerpos Insulínicos/inmunología , Síndromes Paraneoplásicos/inmunología , Feocromocitoma/inmunología , Receptor de Insulina/inmunología , Acantosis Nigricans/patología , Adulto , Diabetes Mellitus/inmunología , Humanos , Resistencia a la Insulina , Masculino , Piel/patologíaRESUMEN
Patients with type B insulin resistance and acanthosis nigricans have autoantibodies to their insulin receptors and usually have signs and symptoms of other autoimmune diseases. The first case demonstrating that hyperalimentation markedly disturbs blood glucose control in type B insulin-resistant patients is described. Neither prednisone, insulin (up to 240 units per hour), nor tolbutamide appeared to help this patient's metabolic control. After the addition of cyclophosphamide for one week, the anti-insulin receptor autoantibody titer dropped from greater than 1:1,000 to 1:1. Six months later, the patient had a complete remission, which is rare, with only three other reported remissions in these patients with type B insulin resistance.
Asunto(s)
Acantosis Nigricans/inmunología , Autoanticuerpos/inmunología , Glucemia/metabolismo , Hiperglucemia/inmunología , Resistencia a la Insulina , Nutrición Parenteral Total/efectos adversos , Receptor de Insulina/inmunología , Adulto , Ciclofosfamida/uso terapéutico , Femenino , Humanos , Hiperglucemia/metabolismo , Hiperglucemia/terapia , Insulina/uso terapéutico , Prednisona/uso terapéutico , Factores de Tiempo , Tolbutamida/uso terapéuticoAsunto(s)
Resistencia a la Insulina , Patología , Receptor de Insulina/fisiología , Acantosis Nigricans/inmunología , Acantosis Nigricans/metabolismo , Animales , Autoanticuerpos/análisis , Diabetes Mellitus/metabolismo , Humanos , Insulina/metabolismo , Ratones , Receptor de Insulina/inmunología , Receptor de Insulina/metabolismo , SíndromeAsunto(s)
Autoanticuerpos/inmunología , Enfermedades Autoinmunes/inmunología , Receptor de Insulina/inmunología , Acantosis Nigricans/inmunología , Acantosis Nigricans/terapia , Animales , Ataxia Telangiectasia/inmunología , Enfermedades Autoinmunes/etiología , Resistencia a Medicamentos , Técnica del Anticuerpo Fluorescente , Humanos , Insulina/farmacología , Ratones , Obesidad/inmunología , Receptor de Insulina/análisis , Receptor de Insulina/aislamiento & purificaciónRESUMEN
A 51-yr-old, nonobese, male patient presented with hyperglycemia and a recent 40-pound weight loss. Severe insulin resistance was documented in studies in which high amounts of insulin were infused using the Biostator GCIIS. Diabetic control was finally achieved with subcutaneous injections of 470 U of insulin per day. Positive laboratory findings included a mild pancytopenia, elevated erythrocyte sedimentation rate, decreased C3 and properdin, and increased IgA. Antinuclear or other autoantibodies were not present. Insulin antibody levels were within the range usually present in insulin-treated diabetic patients. Acanthosis nigricans was not present. Incubation of the patient's serum with IM-9 lymphoblastoid cells revealed that an insulin receptor antibody was present in a serum dilution of 1:80. Insulin-resistant diabetes mediated by insulin receptor antibodies may present in patients with immunologic findings but without overt dermatologic stigmata.
Asunto(s)
Acantosis Nigricans/inmunología , Autoanticuerpos/aislamiento & purificación , Diabetes Mellitus/inmunología , Receptor de Insulina/inmunología , Acantosis Nigricans/diagnóstico , Adulto , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Insulin receptors in human tissue undergo marked changes in both their concentration and their affinity for insulin. In general, alterations in receptor affinity are associated with rapidly changing metabolic environments and can occur within hours, whereas alterations in receptor concentration appear to require longer time periods for their induction. The association of a given type of receptor alteration (i.e., change in affinity or concentration) with a given clinical state indicates the presence of distinct modulators of the insulin-receptor interaction. We have presented evidence for 2 specific modulators, i.e., insulin itself and anti-insulin-receptor antibodies. In several clinical states, especially those associated with changes in receptor affinity, receptor alterations are unrelated to either ambient insulin levels or anti-receptor antibodies, suggesting the presence of several as yet unknown mediators of the insulin receptor. The direct metabolic consequences of these receptor events are not well established. In several states, the receptor alteration correlated quite well with the clinical sensitivity of the whole organism to insulin, indirectly implicating the receptor as the major control point for insulin sensitivity. In contrast, specific examples were cited in which receptor events are not consonant with observed biologic responses to insulin, thereby suggesting a predominance of postreceptor processes. Finally, it should be emphasized that the study of hormone receptors and their relationship to disease states is in the formative stage. With new and improved methodology we hope we will be able to investigate the entire pathway of insulin action at its target tissues, from the initial receptor binding to the final biologic effect.
Asunto(s)
Receptor de Insulina/fisiología , Acantosis Nigricans/inmunología , Acromegalia/metabolismo , Adenoma de Células de los Islotes Pancreáticos/metabolismo , Animales , Anticuerpos , Ataxia/inmunología , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/metabolismo , Humanos , Insulina/farmacología , Resistencia a la Insulina , Obesidad/metabolismo , Neoplasias Pancreáticas/metabolismo , Receptor de Insulina/inmunología , Telangiectasia/inmunologíaRESUMEN
We have previously described a group of young females with virilization, acanthosis nigricans, insulin resistance, and markedly decreased binding of insulin to its receptor (syndrome of insulin resistance and acanthosis nigricans type A). The present report concerns a 15-yr-old female with clinical features indistinguishable from the type A patients, including virilization, acanthosis nigricans, and extreme resistance to endogenous and exogenous insulin. Insulin levels were 400-650 microU/ml while fasting and were over 2200 microU/ml when stimulated. Proinsulin was less than 10% of the total immunoassayable insulin. In distinct contrast to the type A patients, insulin receptors on cells from this patient were entirely normal on the basis of specificity, negative cooperativity, affinity, concentration, and interaction with antiinsulin receptor antibodies. These findings suggest the presence of an intracellular defect as the cause of the observed insulin resistance.