Autoanticuerpos anti-insulina en la diabetes tipo 1 / Anti-insulin autoantibodies in type 1 diabetes

Introducción: Los autoanticuerpos anti-insulina (AAI) representan un marcador serológico de la diabetes tipo 1 (DT1). El significado clínico de los AAI aún no ha sido determinado en la población cubana. Objetivo: Determinar el valor clínico de AAI en pacientes con DT1. Métodos: Se determinaron los niveles séricos de AAI por el ensayo inmuno-adsorbente ligado a enzima (ELISA) en 33 pacientes adultos con DT1, 78 pacientes con otras condiciones endocrinas (CEE) como diabetes tipo 2, tiroiditis de Hashimoto e hiperinsulinemia, y 49 controles normales (CN). El valor de corte se determinó con el análisis de las curvas características operativas del receptor (COR) (ROC por sus siglas en inglés). Se utilizaron pruebas no paramétricas para comparar los niveles de AAI de pacientes con DT1, CEE y CN, y determinar la correlación entre AAI y la edad. Resultados: El valor de corte óptimo de AAI para DT1 fue el índice de 1,05, con sensibilidad de 45,5 por ciento, especificidad de 81,6 por ciento, razón de verosimilitud positiva de 2,47, y razón de verosimilitud negativa de 0,67. Los niveles de AAI en DT1 (índice de 0,97) fueron significativo, más altos que los de CN (índice de 0,70; p=0,020) y los de CEE (índice de 0,63; p= 0,009). Los niveles de AAI resultaron inversamente proporcionales a la edad en pacientes diabéticos ( =-0,252; p=0,030). Conclusiones: Los pacientes con DT1 se distinguieron por niveles más altos de AAI, aunque la presencia de estos anticuerpos no fue exclusiva de DT1. Los niveles de AAI dependieron de la edad en los pacientes diabéticos(AU)

Introduction: Anti-insulin autoantibodies (AAI) represent a serological marker of type 1 diabetes (T1D). The clinical significance of AAIs has not yet been determined in the Cuban population. Objective: To determine the clinical value of AAI in patients with T1D. Methods: AAI serum levels were determined by enzyme-linked immunosorbent assay (ELISA) in 33 adult patients with T1D, 78 patients with other endocrine conditions (CEE) such as type 2 diabetes, Hashimoto's thyroiditis, and hyperinsulinemia, and 49 normal controls (CN). The cut-off value was determined by receiver operating characteristic (ROC) curve analysis. Nonparametric tests were used to compare the AAI levels of patients with T1D, CEE, and CN, and to determine the correlation between AAI and age. Results: AAI optimal cut-off value for T1D was the index of 1.05, with 45.5 percent of sensitivity, 81.6 percent specificity, 2.47 positive likelihood ratio, and 0.67 negative likelihood ratio. AAI levels in DT1 (index of 0.97) were significant, higher than those of CN (index of 0.70; p= 0.020) and CEE levels (index of 0.63; p= 0.009). AAI levels were inversely proportional to age in diabetic patients (ρ = -0.252; p=0.030). Conclusions: Patients with T1D were distinguished by AAI higher levels, although the presence of these antibodies was not exclusive to T1D. AAI levels depended on age in diabetic patients(AU)

Recurrent hypoglycemic coma and diabetic ketoacidosis caused by insulin antibody: a rare case of type 1 diabetes mellitus / Hipoglicemia hiperinsulinémica causada por anticuerpos antiinsulina: informe de un caso

ABSTRACT Insulin antibodies (IAs) induced by exogenous insulin rarely cause hypoglycemia. However, insulin autoantibodies (IAAs) in insulin autoimmune syndrome (IAS) can cause hypoglycemia. The typical manifestations of IAS are fasting or postprandial hypoglycemia, elevated insulin level, decreased C-peptide levels, and positive IAA. We report a 45-year-old male with type 1 diabetes mellitus (T1DM) treated with insulin analogues suffering from recurrent hypoglycemic coma and diabetic ketoacidosis (DKA). His symptoms were caused by exogenous insulin and were similar to IAS. A possible reason was that exogenous insulin induced IA. IA titers were 61.95% (normal: 300 mU/L and < 0.02 nmol/L when hypoglycemia occurred. Based on his clinical symptoms and other examinations, he was diagnosed with hyperinsulinemic hypoglycemia caused by IA. His symptoms improved after changing insulin regimens from insulin lispro plus insulin detemir to recombinant human insulin (Gensulin R) and starting prednisone.

Los anticuerpos contra la insulina (AI) inducidos por la insulina exógena raramente causan hipoglucemia. No obstante, los autoanticuerpos contra la insulina (AIA) en el síndrome autoinmune de insulina (SAI) pueden causar hipoglucemia. Las manifestaciones típicas del SAI son la hipoglucemia en ayunas o posprandial, niveles elevados de insulina, la disminución del nivel de péptido C y AIA positivos. Presentamos un paciente hombre de 45 años con diabetes mellitus de tipo 1 (DMT1) tratado con análogos de insulina, que sufría comas hipoglucémicos recurrentes y cetoacidosis diabética (CAD). Sus síntomas fueron causados por la insulina exógena y fueron similares al SAI. La posible razón fue que la insulina exógena indujo AI. El título de AI era del 61,95% (Normal: 300 mU/L y < 0,02 nmol/L cuando se producía la hipoglucemia. Basados en sus síntomas clínicos y otros exámenes, se le diagnosticó hipoglucemia hiperinsulinémica causada por la AI. Sus síntomas mejoraron después de cambiar el régimen de insulina de lispro más insulina detemir a insulina humana recombinante (Gensulin R) y de empezar a tomar prednisona.

Insulin autoimmune syndrome in an occidental woman: a case report and literature review

SUMMARY Insulin autoimmune syndrome (IAS, Hirata's disease) is a rare hypoglycemic disorder characterized by spontaneous hypoglycemia associated with extremely high circulating insulin levels and positive anti-insulin antibody results. Thus far, most cases have been reported in Asian countries, notably Japan, with few cases reported in western countries. As a possible cause, it is associated with the use of drugs containing sulfhydryl radicals, such as captopril. This report refers to a 63-year-old female Brazilian patient with a history of postprandial hypoglycemia. After extensive investigation and exclusion of other causes, her hyperinsulinemic hypoglycemia was considered to have likely been induced by captopril. Most cases of IAS are self-limiting. However, dietary management, corticosteroids, plasmapheresis, and rituximab have already been used to treat patients with IAS. In our case, after discontinuation of captopril, an initial decrease in insulin autoantibody levels was observed followed by improvement in episodes of hypoglycemia. Although it is a rare disease, IAS should be considered in the differential diagnosis of endogenous hyperinsulinemic hypoglycemia. Patients with suspected IAS must be screened for autoimmunity-related drugs for insulin. Initial clinical suspicion of IAS can avoid unnecessary costs associated with imaging examinations and/or invasive surgical procedures.

Acantosis nigricans y su asociación con insulinorresistencia en población infantil menor a 15 años con sobrepeso u obesidad / Acanthosis nigricans and its association with insulin resistance in children under 15 years of age with overweight or obesity

Contexto: la acantosis nigricans en sujetos adultos con obesidad es un marcador cutáneo de insulinorresistencia.Objetivo: determinar la asociación entre acantosis nigricans e insulinorresistencia en pacientes pediátricos. Sujetos y métodos: estudio de caso-control que evaluó a niños y adolescentes entre 6 a 15 años de edad que asistieron a consulta externa de Dermatología del Hospital Pediátrico Baca Ortiz de Quito, en el período julio a septiembre de 2015. Los pacientes se reclutaron por muestreo no probabilístico, conformándose dos grupos: casos y controles, con 25 sujetos cada uno. Resultados: se determinó en 15 pacientes (60%) con acantosis nigricans presentaron insulinorresistencia; de éstos, se calificó como acantosis nigricans moderada a 6 pacientes (24%) y severa 19 pacientes (76%) siendo más predictivas de insulinorresistencia en sujetos con obesidad (p=0,001). Los pacientes con obesidad y acantosis nigricans severa presentaron un OR de 54 (2,85-99,32) mientras que los pacientes diagnosticados de obesidad y acantosis nigricans moderada presentaron un OR de 12 (1,29-86,20). Conclusión: se encontró que la acantosis nigricans moderada y severa en niños y adolescentes con obesidad constituyo un signo cutáneo de insulinorresistencia. (AU)

Context: acanthosis nigricans in adult subjects with obesity is a cutaneous marker of insulin resistance. Objective: to determine the association between acanthosis nigricans and insulin resistance in pediatric patients. Subjects and methods: a case control study that evaluated children and adolescents between 6 and 15 years of age who attended the outpatient clinic of Dermatology of the Baca Ortiz Pediatric Hospital of Quito, from July to September 2015, were studied. Patients were recruited by non-probabilistic sampling, conforming two groups: cases and controls, with 25 subjects each. Results: it was determined in 15 patients (60%) with acanthosis nigricans presented insulin resistance; Of these, 6 patients (24%) and 19 patients (76%) were classified as moderate acanthosis nigricans, being more predictive of insulin resistance in subjects with obesity (p = 0.001). Patients with severe obesity and acanthosis nigricans had an OR of 54 (2.85-99.32) while patients diagnosed with obesity and moderate acanthosis nigricans had an OR of 12 (1.29-86.20). Conclusion: moderate and severe acanthosis nigricans in children and adolescents with obesity constitutes a cutaneous sign of insulin resistance. (AU)

Síndrome de hipoglicemia autoinmune: Primeros casos en Chile / Insulin autoimmune syndrome: Report of two cases

Insulin autoimmune syndrome (IAS) is characterized by spontaneous hypoglycemia with extremely high insulin levels and the presence of circulating autoantibodies against insulin, in patients who have never been exposed to exogenous insulin. We report two patients with the syndrome. A 36 years old male presenting with hypoglycemia in the emergency room had an oral glucose tolerance test showed basal and 120 min glucose levels of 88 and 185 mg/dl. The basal and 120 min insulin levels were 2,759 and 5,942 μUI/ml. The presence of an insulin secreting tumor was discarded. Anti-insulin antibodies were positive. He was successfully treated with a diet restricted in carbohydrates and frequent meals in small quantities. A 65 years old female presenting with hypoglycemia in the emergency room had the fasting insulin levels of 1,910 µUI/ml. No insulin secreting tumor was detected by images and anti-insulin antibodies were positive. The polyethylene glycol precipitation test showed a basal and after exposition insulin level 1,483 and 114 µUI/ml, respectively. She responded partially to diet and acarbose and required the use of prednisone with a good clinical response.

Asociación de la variante GHRd3 del receptor de la hormona de crecimiento con autoinmunidad en la diabetes tipo 1 / Association of GHRd3 variant of growth hormone receptor gene with autoimmunity in type 1 diabetes

Background: Growth Hormone Receptor (GRH) is expressed in the liver, pancreas, stomach and small intestine. A high expression of GHR mRNA in the mucosal gut suggests a possible role of this receptor on digestive and immune functions. Aim: To investigate the putative effects of the GHRd3 variants on the cytokine profile and distribution of auto-antibodies in children with type 1 diabetes (T1D). Material and Methods: Unrelated unaffected controls (n =192) and incident cases of children with T1D (n =127) were analyzed for GHRd3 polymorphism, cytokine profile and a panel of auto-antibodies. Results: The allele frequency for d3 was 24.8 percent in type 1 diabetics and 34.1 percent in controls (p =NS). Among type 1 diabetic children, the carriers of the GHRd3 polymorphism had significantly higher levels of interleukin-lB than homozygous for the wild type genotype (5.7 and 17.7, pg/ml respectively p <0.015). Carriers of d3 variant had a higher frequency of positive anti-insulin antibodies (anti-IAA) than children without this variant (39.6 and 17.7 percent respectively, p <0.01). Conclusions: The observed frequency of the GHR d3/d3 genotype was comparable to other reports. A relationship between d3 variant and anti-IAA antibodies and interleukin-1ß was observed.

Hiperinsulinismo na infância: quando apenas uma dosagem de insulina não é suficiente / Hyperinsulinism in infancy and childhood: when an insulin level is not always enough

INTRODUÇÃO: A hipoglicemia em bebês e crianças pode causar convulsões, atraso de desenvolvimento e dano cerebral permanente. O hiperinsulinismo (HI) é a causa mais comum de hipoglicemia, seja transitória ou permanente. A HI é caracterizada pela secreção inadequada de insulina, o que resulta em hipoglicemia persistente, de leve a grave. As diferentes formas de HI representam um grupo de doenças clínica, genética e morfologicamente heterogêneo. CONTEÚDO: Hiperinsulinismo congênito está associado às mutações de SUR-1 e Kir6.2, glucoquinase, glutamato desidrogenase, 3-hidroxiacil-CoA desidrogenase de cadeia curta e expressão ectópica de SLC16A1 na membrana plasmática das células beta. O HI pode estar associado ao estresse perinatal, como asfixia do nascimento, toxemia materna, prematuridade ou retardo do crescimento intra-uterino, resultando em hipoglicemia neonatal prolongada. Mimetismo de HI neonatal inclui pan-hipopituitarismo, hipoglicemia induzida por fármaco, insulinoma, anticorpos antiinsulina e estimuladores do receptor de insulina, síndrome de Beckwith-Wiedemann e distúrbios congênitos de glicosilação. Exames laboratoriais para HI podem incluir quantificação de glicose, insulina, β-hidroxibutirato, ácidos graxos, amônia e perfil de acilcarnitinas plasmáticos, além de ácidos orgânicos urinários. Os exames genéticos estão disponíveis em laboratórios comerciais para os genes sabidamente associados à hiperinsulinemia. Testes de resposta insulínica aguda (RIA) são úteis na caracterização fenotípica. Exames de imagem e histológicos também estão disponíveis para diagnosticar e classificar o HI. O objetivo do tratamento de crianças com HI é prevenir os danos cerebrais da hipoglicemia, mantendo níveis de glicose plasmática acima de 70mg/dl por terapia farmacológica ou cirúrgica. CONCLUSÃO:A terapêutica do HI requer abordagem multidisciplinar que inclui endocrinologistas pediátricos, radiologistas, cirurgiões e patologistas, os quais são treinados para diagnosticar..

BACKGROUND: Hypoglycemia in infants and children can lead to seizures, developmental delay, and permanent brain damage. Hyperinsulinism (HI) is the most common cause of both transient and permanent disorders of hypoglycemia. HI is characterized by dysregulated insulin secretion, which results in persistent mild to severe hypoglycemia. The various forms of HI represent a group of clinically, genetically, and morphologically heterogeneous disorders. CONTENT: Congenital hyperinsulinism is associated with mutations of SUR-1 and Kir6.2, glucokinase, glutamate dehydrogenase, short-chain 3-hydroxyacyl-CoA dehydrogenase, and ectopic expression of SLC16A1 on β-cell plasma membrane. Hyperinsulinism may be associated with perinatal stress such as birth asphyxia, maternal toxemia, prematurity or intrauterine growth retardation, resulting in prolonged neonatal hypoglycemia. Mimickers of hyperinsulinism include neonatal panhypopituitarism, drug-induced hypoglycemia, insulinoma, antiinsulin and insulin-receptor stimulating antibodies, Beckwith-Wiedemann Syndrome, and congenital glycosylation disorders. Laboratory testing for hyperinsulinism may include quantification of blood glucose, plasma insulin, plasma β-hydroxybutyrate, plasma fatty acids, plasma ammonia, plasma acylcarnitine profile and urine organic acids. Genetic testing is available at commercial laboratories for genes known to be associated with hyperinsulinism. Acute insulin response (AIR) tests are useful in phenotypic characterization. Imaging and histological tools are also available to diagnose and classify hyperinsulinism. The goal of treatment in infants with hyperinsulinism is to prevent brain damage from hypoglycemia by maintaining plasma glucose levels above 700 mg/l (70 mg/dl) through pharmacologic or surgical therapy. SUMMARY: The treatment of hyperinsulinism requires a multidisciplinary approach that includes pediatric endocrinologists, radiologists, surgeons, and pathologists who trained to diagnose...

The natural history of type 1A diabetes

We can now predict the development of Type 1A (Immune Mediated) diabetes primarily through the determination of four biochemically characterized islet autoantibodies [insulin, GAD65, IA-2 (ICA512) and (Znt8)]. Prediction is possible because beta-cell destruction is chronically progressive and very slow in most, but not all individuals. We can also prevent type 1A diabetes in animal models and a major goal is the prevention of type 1A diabetes in man with multiple clinical trials underway.

Atualmente o desenvolvimento do diabetes melito tipo 1 A( imune mediado) pode ser predito através da determinação de quatro auto-anticorpos antiilhotas [antiinsulina, anti-GAD65, anti-IA2 (ICA512) e (anti-Znt8)] caracterizados bioquimicamente. A predição dessa doença é possível devido a destruição das células-beta, não em todos os indivíduos mas na sua maioria, ser crônica e lentamente progressiva. Também é possível prevenir o DM1 A em modelos animais e o objetivo maior é a prevenção dessa doença em humanos, para os quais vários protocolos clínicos estão em andamento.

Insulin autoimmune syndrome: case report

CONTEXTO: A síndrome da hiperinsulinemia autoimune (SHA, doença de Hirata) é uma causa rara de hipoglicemia nos países ocidentais. Ela é caracterizada por episódios de hipoglicemia, níveis elevados de insulina e presença de anticorpos anti-insulina. Nosso objetivo é relatar um caso da SIA identificado na América do Sul. RELATO DO CASO: Um homem caucasiano de 56 anos de idade começou a apresentar sintomas neuroglicopênicos durante hospitalização devida a trauma grave. A avaliação laboratorial confirmou hipoglicemia e níveis extremamente elevados de insulina. Os exames radiológicos convencionais realizados foram negativos para tumor pancreático. A remissão clínica da doença não ocorreu durante o uso de verapamil e corticóides. Desta forma, pancreatectomia subtotal foi realizada devido à ausência de resposta ao tratamento conservador e à impossibilidade de serem utilizados imunosupressores em razão da bacteremia persistente. O exame histopatológico revelou hiperplasia difusa de células beta. O paciente persiste apresentando níveis elevados de insulina porém praticamente não apresenta mais episódios de hipoglicemia.

Resistência insulínica imunológica: apresentação de caso / Immunologic insulin resistance: case report

Resistência insulínica imunológica é uma entidade reconhecida na prática clínica há muitos anos. Sua patogênese está relacionada ao aparecimento de anticorpos anti-insulina, e o tratamento baseia-se em imunossupressão. Apresentamos aqui o caso de uma paciente de 33 anos, com diagnóstico de diabetes desde a infãncia, que referia uso de hipoglicemiantes orais durante a adolescência. Durante o acompanhamento em nosso serviço, a dose de insulina foi progressivamente reduzida até ser substituída por hipoglicemiantes orais. Permaneceu 11 meses com esquema de glibenclamida, mefformina e acarbose até ser internada em coma hiperosmolar não-cetótico. Após internação prolongada, recebeu alta usando insulina NPH, sendo necessário o aumento da dose nos meses subseqüentes. Quando atingiu a dose de 2,7U/Kg/dia, foi investigada e excluída a possibilidade de diabetes secundário, sendo diagnosticada resistência insulínica imunológica. Foram tentados diversos esquemas imunossupressores sem sucesso. A paciente está atualmente em uso de bomba de infusão subcutânea de insulina Lispro, micofenolato mofetil e prednisona com melhora do controle glicêmico.

Marcadores inmunológicos y genéticos en diabetes mellitus tipo 1 en Argentina / Immunologic and genetic markers in type 1 diabetes mellitus in Argentina

El objetivo del trabajo fue evaluar la prevalencia y asociación de los marcadores inmunológicos (anticuerpo anti-islote pancreático: ICA, autoanticuerpo anti-insulina: IAA, anticuerpo antidecarboxilasa del ácido glutámico: GADA y anticuerpo anti ICA512) y con el genotipo HLA DQBl en pacientes con diabetes tipo 1 de reciente debut, hermanos de diabéticos y personas sin historia de enfermedad autoinmune en población argentina. Se estudiaron 79 niños con diabetes tipo 1 de reciente debut, 79 niños controles y 68 hermanos sanos de niños con diabetes 1. En todos ellos se determinó IAA, GADA, ICA, ICA512 y alelos HLA DQB1. La sensibilidad para ICA fue de 67.1 por ciento; para IAA de 36,7 por ciento; para GADA de 74,6 por ciento, y para ICA512 de 63,4 por ciento. Ninguno de los niños control presentó marcadores inmunológicos positivos. La sensibilidad combinada de ICA-IAA-GADA fue de 89,8 por ciento, similar a la de ICA512-GADA (87.3 por ciento) o la combinación de ICA512-GADA-IAA (91.1 por ciento). El valor de GADA presentó correlación positiva con el de ICA, no encontrándose correlación alguna entre los valores de IAA, ICA512 e ICA. El valor de IAA presentó correlación negativa y el de GADA positiva con la edad de los pacientes. La presencia de IAA se asoció con DQB1 *0201, mientras que la de ICA e ICA512 con DQB1 *0302. Entre los hermanos, 3/68 (4,4 por ciento) fueron positivos para IAA, uno (1,5 por ciento) lo fue para GADA y otro (1.5 por ciento) para ICA512. Nuestros resultados muestran que la combinación de múltiples marcadores incrementa la sensibilidad predictiva, siendo la asociación ICA512-GADA altamente sensible y equivalente a otras combinaciones propuestas como ICA-IAA-GADA

Autoinmunidad de las células beta del páncreas y riesgo de progresión a diabetes tipo I / Pancreatic beta cell autoimmunity and the risk of progression to type 1 diabetes

La diabetes tipo 1 es una enfermedad autoinmune, caracterizada por la carencia absoluta de insulina. Si bien muchos aspectos de la fisiopatología aún no están resueltos, se sabe que en el período prodrómico, cuando todavía no hay síntomas de la enfermedad, se encuentran autoanticuerpos contra diferentes estructuras de las células betapancreáticas. Hasta el momento se cuenta con métodos bioquímicos para dosar ICA (anticuerpo contra células del islote), GADA (anticuerpo contra glutamato decarboxilasa), IA-2 (anticuerpo contra tirosin fosfatasa), e IAA (anticuerpo anti insulina), siendo el riesgo significativamente mayor cuando tres o cuatro autoanticuerpos resultan positivos. El dosaje de estos autoanticuerpos y los alelos HLA-DQB 0203/0302 permiten identificar a las personas con alto riesgo de desarrollar DBT-1 durante los siguientes 5 a 10 años. Por el contrario, el hallazgo de HLA-DQB1 0602/0603 funciona de alguna manera con alelos protectores. En estudios más recientes, se ha investigado la utilidad del dosaje de anticuerpos en pacientes con trasplante de páncreas o de islotes para evaluar el comportamiento de las células trasplantadas y como predictores de rechazo

Perfil de auto anticuerpos y lactancia materna en pacientes diabéticos tipo 1 / Auto-antibody levels and history of breast-feeding in type 1 diabetic patients

Background: Islet cell-specific autoantibodies such as islet cell antibody (ICA), antiinsulin (IAA), anti-glutamic acid decarboxylase (GAD) and anti-tyrosine phosphatase (IA2) can be present in patients with type I diabetes. Breast feeding duration and the early exposure to milk substitutes are environmental factors associated to etiology of type 1 diabetes. Aim To study the frequency of the anti-GAD, anti-IA-2 e ICA antibodies in Chilean type 1 diabetic patients and determine the possible modulator effect of the breast feeding. Patients and methods: One hundred thirty four type I diabetic patients, aged one to 15 years old, were studied at the moment of their diagnosis. Patients were classified according to the duration of exclusive breast feeding. IA-2 and GAD were determined by radio immuno assay and ICA by means of indirect immunofluorescence. Results: Subjects with three months or less and those with more than three months of breast feeding were positive for ICA in 78.8 and 90.6 per cent of cases respectively, for GAD in 75 and 54.6 per cent of cases respectively (p=0.024) and for IA-2 in 73 and 43.8 per cent of cases respectively (p=0.001). All three antibodies were positive in 53.9 and 21.8 per cent of children with less or more than three months of breast feeding (p=0.001). Conclusion: Both IA-2 and GAD antibodies are less frequently positive in type 1 diabetic patients who have been breast fed for more than three months. These findings suggest a possible attenuating role of exclusive breast feeding on pancreatic aggression events in patients with type 1 diabetes

Frequency of islet cell autoantibodies (IA-2 and GAD) in young Brazilian type 1 diabetes patients

Type 1 diabetes, as an autoimmune disease, presents several islet cell-specific autoantibodies such as islet cell antibody (ICA), anti-insulin, anti-glutamic acid decarboxylase (GAD) and the antibody (Ab) against tyrosine phosphatase (PTP)-like protein known as ICA-512 (IA-2). In order to determine the frequency of the anti-GAD and anti-IA-2 autoantibodies in Brazilian type 1 diabetes patients we studied 35 diabetes mellitus (DM) type 1 patients with recent-onset disease 12 months and 37 type 1 diabetes patients with long-duration diabetes 12 months who were compared to 12 children with normal fasting glucose. Anti-GAD65 and anti-IA-2 autoantibodies were detected with commercial immunoprecipitation assays. The frequency of positive results in recent-onset DM type 1 patients was 80.0 percent for GADAb, 62.9 percent for IA-2Ab and 82.9 percent for GADAb and/or IA-2Ab. The long-duration type 1 diabetes subjects presented frequencies of 54.1 percent for GADAb and IA-2Ab, and 67.5 percent for GAD and/or IA-2 antibodies. The control group showed no positive cases. Anti-GAD and IA-2 assays showed a high frequency of positivity in these Brazilian type 1 diabetes patients, who presented the same prevalence as a Caucasian population

Auto Anticorpos anti-ilhota e anti-insulina em diabéticos do tipo 1 de diagnóstico recente e parentes de primeiro grau brasileiros / Autoantibodies anti-islets and anti-insulin in patients with recently dianosed type I diabetes and in Brazilian first degree relatives

Os autoanticorpos contra as células pancreáticas têm sido utilizados para caracterizar e determinar o risco de evoluçao para o diabetes mellitus do tipo 1 (DM1) autoimune. No entanto, a maioria desses estudos foram realizados em populaçoes norte-americanas, européias ou asiáticas. No presente estudo foram avaliadas, em brasileiros, as prevalências dos autoanticorpos anti-ilhota (ICA) e anti-insulina (IAA) em normais (N), DM1 com início recente - menos de 6 meses de diagnóstico (DM1ir) e parentes de primeiro grau de DM1, nao diabéticas (PGDM1). Os métodos utilizados foram: imunohistoquímica (imunoperoxidade-proteína A) para os ICA e radioensaio supersensível para os IAA. A prevalência dos ICA isoladamente foi: N= 2,1 por cento (1/48), PGDM1= 5,6 por cento (3/54), DM1ir= 68 por cento (50/74) e dos IAA: N= 0 por cento (0/17), PGDM1= 18,7 por cento (27/144), DM1ir= 47,5 por cento (29/61); e de ambos. ICA+IAA, foi: N= 0 por cento (0/17), PGDM1= 1,8 por cento (1/54), DM1ir= 36 por cento (9/53). A positividade dos ICA (p<0,001), dos IAA (p<0,001) e de ambos (p<0,001) foi mais prevalente nos DM1ir. OS ICA foram mais prevalentes nos DM1ir entre 5 e 15 anos do que naqueles com idade superior a 30 anos por ocasiao do diagnóstico (p=0,003). Há uma correlaçao inversa (rS= -0,42, p<0,001) entre os níveis de IAA e a idade ao diagnóstico. Os níveis de IAA nos DM1ir (165,9+33,7 nU/ml; X+EPM) foram maiores do que nos N (22,3+2,5 nU/ml;p<0,001) e nos PGDM1 (508,7 nU/ml; p=0,03). Esses resultados mostram uma alta prevalência de autoimunidade nos DM1 da populaçao brasileira. A prevalência dos ICA e a distribuiçao dos IAA entre as faixas etárias dos DM1ir foram semelhantes às encontradas em populaçoes pareadas de outros países. Assim, também no nosso meio, os ICA e os IAA podem ser utilizados para o diagnóstico do DM1 autoimune. Estudos longitudinais de crianças com ICA ou IAA positivos sao necessários no nosso país para se determinar o valor preditivo destes anticorpos para a doença manifesta.

Sindrome de hipoglucemia autoinmune con anticuerpos especificos anti-insulina humana / Autoimmune hypoglycemia syndrome with specific anti-human insulin antibodies

Se presenta una mujer de 33 años con una historia l1 meses de episodios recurrentes de hipoglucemia severa, asociados a anticuerpos anti-insulina y valores variables de peptido-C. Una extracción ácido-alcohólica de suero mostró un nível basal de insulina de 1.600 uU/ml. La insulina caracterizada por HPLC demostró ser insulina humana. Los anticuerpos fueron específicos para la insulina humana con una subpoblación que reaccionaba con insulina bovina y porcina (IgG, cadena liviana k). Al declinar los síntomas, el tratamiento con plasmaféresis negativizó el título con rapidez. Un seguimiento prolongado demostró la ausencia de recidivas.

Comparison of the determination of insulin by a monoclonal antibody-based immunofluorometric assay and by radioimmunoassay

This paper describes an immunofluorometric assay (IFMA) for insulin and compares it with the classical radioimmunoassay (RIA). Monoclonal antibodies against insulin were produced and used to develop the IFMA. One, immobilized on microtiter plates, was used for capture, the other, labelled with Europium, was used as tracer antibody. The IFMA presentes sensitivity to an amount of insulin of 3 pmol/1 and acceptable valueus for intra- and interassay error. The IFMA presented superimposable curves for human insulin, Arg65/Gly66-split proinsulin and des-Lys64, Arg65, and no cross-reactivity with human proinsulin, Arg32/Glu33 -split and des-Arg31, Arg32. The RIA showed 100 percent cross-reactivity with human proinsulin, 90 pecent with des-Arg31, Arg32 and 170 percent with des-Lys64, Arg65. The assay were used to measure insulin in 300 serum samples from 50 subjects submitted to an oral glucose tolerance test (OGTT). Twenty were normal, 10 had impaired glucose tolerance and 20 non-insulin-dependent diabetes mellitus. The mean value (ñ SEM) obtained bu IFMA was 166.7 ñ 12.1 pmol/1 and the mean value obtained by RIA was 339.6 ñ 18.6, with a correlacion of r = 0.80 (P0.01). Comparison of basal insulin levels of the different groups of individuals using IFMA or RIA led to the same conclusions. The area under curve showed statistically significant differences only for the comparison between normal lean subjects and individuals with impaired glucose tolerance, when measured by RIA...(au)

Cetoacidose diabética desencadeada por resistência imunológica à insulina / Diabetic ketoacidosis induced by immunologic insulin resistance

A cetoacidose diabética (CAD) é a emergência endocrinológica mais freqüente e de boa evoluçäo, na maior parte dos casos. Os autores apresentam evoluçäo atípica de três casos de CAD precipitada por resistência imunológica à insulina (RII). RELATO DE CASO. Três pacientes: H.M.L. (46 anos, diabetes mellitus (DM) tipo II, há 6 anos), D.R.J (39 anos, DM, secundário à pancreatopatia, há 11 anos) e D.L.S. (54 sanos, DM tipo II, há 9 anos) foram admitidos na Unidade de primeiro Atendimento do Hospital Säo Paulo em CAD: H.M.L. (glicemia: 716mg/dL, pH: 6,8), D.R.J. (glicemia: 684mg/dL, pH 6,.9) e D.L.S. (glicemia: 384mg/dL, pH: 7,2), todos apresentavam cetonúria. As necessidades de insulina para o controle metabólico foram: H.M.L.: 1.369UI, D.R.J.: 1.496UI, D.I.S. 1.369UI em, respectivamente: 212, 206 e 72 horas. Os anticorpos antiinsulina (AI) foram dosados por RE e ELISA: H.M.L.: 7.186nU/ml, 3,6IE; D.R.J.: 7,879nU/mL, 3,24IE; D.I.S: 8.377nU/mL, 2,88IE. O seguimento ambulatorial revelou queda progressiva dos níveis de AI:H.M.L.: 3.393nU/mL, 1,39, após dez meses da CAD; d.r.j.: 4,673Nu/Ml, 2,34 E d.i.s.: 1,510nU/mL, ambos após 18 meses da CAD. A queda nos níveis de anticorpos foi significativa nos três pacientes e foi acompanhada de melhor controle metabólico. Discussäo. A ausência de fator desencadeante, o elevado tempo, as altas doses de insulina empregadas para a compensaçäo metabólica levaram os autores à suspeita diagnóstica de RII. O diagnóstico foi confirmado pelos altos níveis séricos dos AI. O controle metabólico nestes pacientes foi obtido somente após a introduçäo de insulina na humanizada. CONCLUSAO. A resistência imunológica à insulina pode ser uma das causas de CAD sem fator precipitante aparente e má resposta às medidas terapêuticas habituais

Evaluación del fenómeno autoinmune y de las alteraciones metabolicas consecuentes durante el inicio de la diabetes mellitus insulino dependiente / Evaluation of the autoimmune phenomenon and the metabolies allerations consecuent during of the insulin dependent diabetes mellitus start

La Diabetes Mellitus Insulino Dependiente (DMID), se considera un desorden autoinmune de génesis multifactorial. La participación tumoral y celular en este fenómeno es fundamental, ya que la inactivación total o parcial de la células ß de los Islotes de Langherhans, depende del efecto que causen sobre ellas los diferentes Autoanticuerpos Antiislotes (ICAs), Autoanticuerpos Antiinsulina (IAA) y los Linfocitos Infiltrantes de los Islotes (ICIL). Existen haplotipos del Sistema HLA que confieren susceptibilidad para la DMID y otros que poseen acción protectora. La evaluación de las poblaciones de riesgo debe efectuarse a través de la detección de los citados anticuerpos, de la definición de los HLA (Regiones DR y DQ) y mediante estudios dinámicos que demuestren la reserva metabólica pancreática, tales como la Curva de Tolerancia Glucosada Endovenosa y la detección del Péptido C

Detection of insulin antibodies by radioassay and ELISA: interrelation and correlation with metabolic control in type I diabetes

1. The literature suggests that the radioassay (RA) and ELISA detect different types of insulin antibodies (IA) (Wilkin et al., 1989. Diabetes, 38: 172-181). 2. In the present study we evaluated the relationship between these two antibodies and their involvement in the metabolic control of Type I diabetic (DMI) patients. 3. IA were measured by RA and ELISA in sera obtained from 34 patients (age: 9-16 years, median = 12.5 years; clinical duration of DMI: 0.1-11.0 years, median = 1.7 years) treated with different types of insulin [purified (bovine + porcine) N = 18, and monocomponent (porcine or human) N = 16] and submitted to various degrees of metabolic control as assessed by glycosylated serum protein (GSP) levels: range, 3.4-13.5; median = 8.7; normal value, 0.8-2.4. 4. Insulin antibody levels measured by RA were: 3264 +/- 300 nU/ml (mean +/- SEM, normal value < 60 nU/ml) and by ELISA: 0.74 +/- 0.11 ELISA index (EI) (normal value, < 0.53). No correlation was found between IA levels measured by RA and ELISA, or between duration of the disease or insulin daily necessity and IA by either method. GSP was positively correlated with IA determined by ELISA (rS = 0.43, P < 0.01) but not with IA determined by RA. 5. The patients on purified bovine + porcine insulin had higher titers of IA by ELISA, compared to those of patients on monocomponent (0.96 +/- 0.15 vs 0.50 +/- 0.13 EI, P < 0.03, while IA levels measured by RA did not differ between groups. 6. These data show that RA or ELISA assays provide different serum titers of IA in insulin-treated diabetics and data obtained with ELISA correlated best with the metabolic control of Type I diabetic patients.