RESUMO
Patients with adult-onset autoimmune diabetes have less Human Leucocyte Antigen (HLA)-associated genetic risk and fewer diabetes-associated autoantibodies compared with patients with childhood-onset Type 1 diabetes. Metabolic changes at diagnosis reflect a broad clinical phenotype ranging from diabetic ketoacidosis to mild non-insulin-requiring diabetes, also known as latent autoimmune diabetes of the adult (LADA). This latter phenotype is the most prevalent form of adult-onset autoimmune diabetes and probably the most prevalent form of autoimmune diabetes in general. Although LADA is associated with the same genetic and immunological features as childhood-onset Type 1 diabetes, it also shares some genetic features with Type 2 diabetes, which raises the question of genetic heterogeneity predisposing to this form of the disease. The potential value of screening patients with adult-onset diabetes for diabetes-associated autoantibodies to identify those with LADA is emphasized by their lack of clinically distinct features, their different natural history compared with Type 2 diabetes and their potential need for a dedicated management strategy. The fact that, in some studies, patients with LADA show worse glucose control than patients with Type 2 diabetes, highlights the need for further therapeutic studies. Challenges regarding classification, epidemiology, genetics, metabolism, immunology, clinical presentation and treatment of LADA were discussed at a 2014 workshop arranged by the Danish Diabetes Academy. The presentations and discussions are summarized in this review, which sets out the current ideas and controversies surrounding this form of diabetes.
Assuntos
Doenças Autoimunes/diagnóstico , Diabetes Mellitus/diagnóstico , Adulto , Idade de Início , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/fisiopatologia , Autoimunidade , Diabetes Mellitus/genética , Diabetes Mellitus/imunologia , Diabetes Mellitus/fisiopatologia , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 2/diagnóstico , Diagnóstico Diferencial , Predisposição Genética para Doença , HumanosRESUMO
AIMS: To explore insulin sensitivity and insulin secretion in people with latent autoimmune diabetes in adulthood (LADA) compared with that in people with type 2 diabetes. METHODS: A total of 12 people with LADA, defined as glutamic acid decarboxylase (GAD) antibody positivity and > 1 year of insulin independency (group A) were age-matched pairwise to people with type 2 diabetes (group B) and to six people with type 2 diabetes of similar age and BMI (group C). ß-Cell function (first-phase insulin secretion and assessment of insulin pulsatility), insulin sensitivity (hyperinsulinemic-euglycemic clamp) and metabolic response during a mixed meal were studied. RESULTS: Both first-phase insulin secretion and insulin release during the meal were greater (P = 0.05 and P = 0.009, respectively) in type 2 diabetes as compared with LADA; these differences were lost on adjustment for BMI (group C) and could be explained by BMI alone in a multivariate analysis. Neither insulin pulsatility, incretin secretion nor insulin sensitivity differed among the groups. CONCLUSIONS: We found no evidence that LADA and type 2 diabetes were distinct disease entities beyond the differences explained by BMI.
Assuntos
Doenças Autoimunes/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Resistência à Insulina , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Adulto , Idade de Início , Autoanticorpos/análise , Doenças Autoimunes/complicações , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/epidemiologia , Glicemia/análise , Índice de Massa Corporal , Estudos de Coortes , Estudos Transversais , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Técnica Clamp de Glucose , Glutamato Descarboxilase/antagonistas & inibidores , Humanos , Hipoglicemiantes/uso terapêutico , Incretinas/sangue , Incretinas/metabolismo , Insulina/sangue , Insulina/uso terapêutico , Secreção de Insulina , Células Secretoras de Insulina/efeitos dos fármacos , Análise por Pareamento , Obesidade/complicações , Sobrepeso/complicações , Período Pós-PrandialRESUMO
AIMS: C-peptide secretion is currently the only available clinical biomarker to measure residual ß-cell function in type 1 diabetes. However, the natural history of C-peptide decline after diagnosis can vary considerably dependent upon several variables. We investigated the shape of C-peptide decline over time from type 1 diabetes onset in relation to age at diagnosis, haemoglobin A1c (HbA1c) levels and insulin dose. METHODS: We analysed data from 3929 type 1 diabetes patients recruited from seven European centres representing all age groups at disease onset (childhood, adolescence and adulthood). The influence of the age at onset on ß-cell function was investigated in a longitudinal analysis at diagnosis and up to 5-years follow-up. RESULTS: Fasting C-peptide (FCP) data at diagnosis were available in 3668 patients stratified according to age at diagnosis in four groups (<5 years, n = 344; >5 years < 10 years, n = 668; >10 years < 18 years, n = 991; >18 years, n = 1655). FCP levels were positively correlated with age (p < 0.001); the subsequent decline in FCP over time was log-linear with a greater decline rate in younger age groups (p < 0.0001). CONCLUSIONS: This study reveals a positive correlation between age at diagnosis of type 1 diabetes and FCP with a more rapid decline of ß-cell function in the very young patients. These data can inform the design of clinical trials using C-peptide values as an end-point for the effect of a given treatment.
Assuntos
Envelhecimento , Peptídeo C/sangue , Diabetes Mellitus Tipo 1/metabolismo , Hipoglicemiantes/uso terapêutico , Anticorpos Anti-Insulina/sangue , Células Secretoras de Insulina/metabolismo , Insulina/uso terapêutico , Adolescente , Adulto , Fatores Etários , Idade de Início , Envelhecimento/metabolismo , Biomarcadores/sangue , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/tratamento farmacológico , Relação Dose-Resposta a Droga , Europa (Continente) , Jejum , Feminino , Seguimentos , Humanos , Estudos Longitudinais , MasculinoRESUMO
Immune-mediated (auto-immune) Type 1 diabetes mellitus is not a homogenous entity, but nonetheless has distinctive characteristics. In children, it may present with classical insulin deficiency and ketoacidosis at disease onset, whereas autoimmune diabetes in adults may not always be insulin dependent. Indeed, as the adult-onset form of autoimmune diabetes may resemble Type 2 diabetes, it is imperative to test for diabetes-associated autoantibodies to establish the correct diagnosis. The therapeutic response can be predicted by measuring the levels of autoantibodies to various islet cell autoantigens, such as islet cell antibodies (ICA), glutamate decarboxylase 65 (GAD65), insulin, tyrosine phosphatase (IA-2) and IA-2ß, and zinc transporter 8 (ZnT8) and evaluating ß-cell function. A high risk of progression to insulin dependency is associated with particular genetic constellations, such as human leukocyte antigen risk alleles, young age at onset, the presence of multiple autoantibodies, including high titres of anti-GAD antibodies; such patients should be offered early insulin replacement therapy, as they respond poorly to diet and oral hypoglycaemic drug therapy. Hence, considering the broad spectrum of phenotypes seen in adult-onset diabetes, treatment targets can only be reached by identification of immune-mediated cases, as their management differs from those with classical Type 2 diabetes.
Assuntos
Autoanticorpos/imunologia , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 2/diagnóstico , Glutamato Descarboxilase/imunologia , Células Secretoras de Insulina/metabolismo , Adolescente , Adulto , Idade de Início , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/imunologia , Diagnóstico Diferencial , Progressão da Doença , Feminino , Predisposição Genética para Doença , Antígenos HLA-DQ/imunologia , Humanos , Lactente , Masculino , Fenótipo , Medição de RiscoRESUMO
AIMS: Systemic concentrations of adhesion molecules and chemokines are associated with increased risk of cardiovascular complications. We compared these factors between patients with Type 2 diabetes vs. Type 1 diabetes or latent autoimmune diabetes in adults. METHODS: Serum concentrations of adhesion molecules sE-selectin, sICAM-1 and sVCAM-1, and chemokines CCL2, CCL3 and CCL4 were measured in 61 patients with latent autoimmune diabetes in adults, 90 with Type 1 diabetes, 465 with Type 2 diabetes and in 41 control subjects, using multiple regression models to adjust for possible confounders. RESULTS: Patients with Type 2 diabetes exhibited greater concentrations of adhesion molecules (P < 0.02) than those with Type 1 diabetes, latent autoimmune diabetes in adults and control subjects. These differences persisted upon adjustments for age, sex, BMI, blood pressure and diabetes duration (P < 0.04). Higher BMI positively correlated with concentrations of adhesion molecules in all subjects (P < 0.0001). Concentrations of sE-selectin positively related to diastolic (ß = 0.31) and systolic (ß = 0.28) blood pressure in the adjusted model (P < 0.04). Concentrations of the chemokines, CCL2 and CCL4, did not differ between groups, while CCL3 was higher in patients with latent autoimmune diabetes in adults and Type 1 diabetes than in those with Type 2 diabetes and control subjects (P < 0.05). CONCLUSIONS: Systemic concentrations of adhesion molecules, but not chemokines, relate to cardiovascular risk factors, but remain higher after adjustments in Type 2 diabetes, suggesting a diabetes-type specific effect without difference between latent autoimmune diabetes in adults and Type 1 diabetes, despite their dissimilar phenotype.
Assuntos
Doenças Cardiovasculares/sangue , Quimiocinas/sangue , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 2/sangue , Angiopatias Diabéticas/sangue , Molécula 1 de Adesão de Célula Vascular/sangue , Adulto , Idoso , Pressão Sanguínea , Índice de Massa Corporal , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/fisiopatologia , Estudos Transversais , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/fisiopatologia , Diabetes Mellitus Tipo 2/imunologia , Diabetes Mellitus Tipo 2/fisiopatologia , Angiopatias Diabéticas/imunologia , Angiopatias Diabéticas/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , FenótipoRESUMO
Type 1 diabetes mellitus (T1DM) is due, in part, to non-genetically determined factors including environmental factors. The nature of these environmental effects remains unclear but they are important to identify since they may be amenable to therapy. Recently, the gut microbiota, the trillions of microorganisms inhabiting the gut, as well as diet, have been implicated in T1DM pathogenesis. Since dietary changes can reshape this complex gut community, its co-evolution could have been altered by changes to our diet, agriculture, personal hygiene, and antibiotic usage, which coincide with the increased incidence of T1DM. Recent studies demonstrate an association between altered gut microbiota and T1DM in both T1DM patients and animal models of the disease. Further studies should provide new insight into those critical host-microbial interactions, potentially suggesting new diagnostic or therapeutic strategies for disease prevention.
Assuntos
Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/microbiologia , Trato Gastrointestinal/metabolismo , Refeições/fisiologia , Animais , Doenças Autoimunes/genética , Doenças Autoimunes/metabolismo , Diabetes Mellitus Tipo 1/genética , Trato Gastrointestinal/microbiologia , HumanosRESUMO
Type 1 diabetes most commonly presents in adulthood, contrary to the widely held view that it is a disease of childhood. Furthermore, a substantial proportion of cases of adult-onset type 1 diabetes does not require insulin therapy at clinical onset. Recent studies have emphasised the evidence that adult-onset type 1 diabetes is prevalent but often misclassified initially as type 2 diabetes (1, 2). In this review, we discuss that recent literature, highlighting the similarities and differences between adult-onset and childhood-onset type 1 diabetes, exploring recent debates surrounding its epidemiology and genetics, as well as expanding on important issues of diagnostic criteria for individuals presenting with adult-onset diabetes and the subsequent management once identified as having an autoimmune basis. In addition, this review looks at the psychosocial challenges faced by T1D patients and their possible management.
Assuntos
Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Adulto , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Humanos , Insulina/uso terapêuticoRESUMO
AIMS/HYPOTHESIS: Systemic pro- and anti-inflammatory cytokines are associated with both type 1 and type 2 diabetes, while their role in latent autoimmune diabetes in adults (LADA) is unclear. Therefore, we compared cytokine concentrations in patients with LADA, type 1 or type 2 diabetes and healthy individuals to test the hypothesis that differences of cytokine concentrations between all groups are attributable to diabetes type and BMI. METHODS: The pro-inflammatory cytokines IL-6 and TNF-α, and the anti-inflammatory cytokines IL-1 receptor antagonist (IL-1RA) and IL-10 were measured in 90 participants with type 1 diabetes, 61 with LADA, 465 with type 2 diabetes and 41 control participants using multiple regression models adjusted for BMI, sex, age, blood pressure and diabetes duration. RESULTS: Patients with type 2 diabetes had higher concentrations of systemic IL-1RA, IL-6 and TNF-α cytokines than patients with either LADA or type 1 diabetes (p < 0.0001 for all differences). Cytokine concentrations in controls were lower than those in all diabetes types (p < 0.04). Increased BMI was positively associated with higher systemic cytokine concentrations in all diabetes types (p < 0.0001). Despite the association of cytokines with anthropometric data, differences between diabetes forms persisted also after adjusting analysis for the confounders BMI, age, sex, disease duration and blood pressure (p < 0.04). CONCLUSIONS/INTERPRETATION: Although body mass associates positively with pro- and anti-inflammatory cytokine levels, patients with type 2 diabetes have higher cytokine levels independent of the prevailing BMI. LADA and type 1 diabetes could not be distinguished by systemic cytokines.
Assuntos
Citocinas/sangue , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 2/sangue , Adulto , Idoso , Feminino , Humanos , Proteína Antagonista do Receptor de Interleucina 1/sangue , Interleucina-10/sangue , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/sangueAssuntos
Diabetes Mellitus Tipo 2/terapia , Guias de Prática Clínica como Assunto , Medicina de Precisão/normas , Qualidade da Assistência à Saúde/normas , Terapia Combinada/normas , Diabetes Mellitus Tipo 2/tratamento farmacológico , Governo Federal , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/uso terapêutico , Reino UnidoRESUMO
Monocytes infiltrate islets in non-obese diabetic (NOD) mice. Activated monocyte/macrophages express cyclo-oxygenase-2 (COX-2) promoting prostaglandin-E(2) (PGE(2)) secretion, while COX-1 expression is constitutive. We investigated in female NOD mice: (i) natural history of monocyte COX expression basally and following lipopolysaccharide (LPS) stimulation; (ii) impact of COX-2 specific inhibitor (Vioxx) on PGE(2), insulitis and diabetes. CD11b(+) monocytes were analysed for COX mRNA expression from NOD (n = 48) and C57BL/6 control (n = 18) mice. NOD mice were treated with either Vioxx (total dose 80 mg/kg) (n = 29) or methylcellulose as control (n = 29) administered by gavage at 4 weeks until diabetes developed or age 30 weeks. In all groups, basal monocyte COX mRNA and PGE(2) secretion were normal, while following LPS, after 5 weeks of age monocyte/macrophage COX-1 mRNA decreased (P < 0.01) and COX-2 mRNA increased (P < 0.01). However, diabetic NOD mice had reduced COX mRNA response (P = 0.03). Vioxx administration influenced neither PGE(2), insulitis nor diabetes. We demonstrate an isoform switch in monocyte/macrophage COX mRNA expression following LPS, which is altered in diabetic NOD mice as in human diabetes. However, Vioxx failed to affect insulitis or diabetes. We conclude that monocyte responses are altered in diabetic NOD mice but COX-2 expression is unlikely to be critical to disease risk.
Assuntos
Diabetes Mellitus Experimental/enzimologia , Monócitos/enzimologia , Prostaglandina-Endoperóxido Sintases/biossíntese , Animais , Células Cultivadas , Ciclo-Oxigenase 1/biossíntese , Ciclo-Oxigenase 1/genética , Ciclo-Oxigenase 2/biossíntese , Ciclo-Oxigenase 2/genética , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/prevenção & controle , Regulação para Baixo , Feminino , Regulação Enzimológica da Expressão Gênica , Lactonas/uso terapêutico , Lipopolissacarídeos/imunologia , Proteínas de Membrana/biossíntese , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Prostaglandina-Endoperóxido Sintases/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Sulfonas/uso terapêutico , Regulação para CimaRESUMO
Type I diabetes (T1D) is a T cell-mediated autoimmune disease characterized by loss of tolerance to islet autoantigens, leading to the destruction of insulin-producing beta cells. Peripheral tolerance to self is maintained in health through several regulatory mechanisms, including a population of CD4+CD25hi naturally occurring regulatory T cells (T(regs)), defects in which could contribute to loss of self-tolerance in patients with T1D. We have reported previously that near to T1D onset, patients demonstrate a reduced level of suppression by CD4+CD25hi T(regs) of autologous CD4+CD25- responder cells. Here we demonstrate that this defective regulation is also present in subjects with long-standing T1D (> 3 years duration; P = 0.009). No difference was observed in forkhead box P3 or CD127 expression on CD4+CD25hi T cells in patients with T1D that could account for this loss of suppression. Cross-over co-culture assays demonstrate a relative resistance to CD4+CD25hi T(reg)-mediated suppression within the CD4+CD25- T cells in all patients tested (P = 0.002), while there appears to be heterogeneity in the functional ability of CD4+CD25hi T(regs) from patients. In conclusion, this work demonstrates that defective regulation is a feature of T1D regardless of disease duration and that an impaired ability of responder T cells to be suppressed contributes to this defect.
Assuntos
Diabetes Mellitus Tipo 1/imunologia , Tolerância a Antígenos Próprios/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Contagem de Linfócito CD4 , Proliferação de Células , Células Cultivadas , Técnicas de Cocultura , Fatores de Transcrição Forkhead/sangue , Humanos , Subunidade alfa de Receptor de Interleucina-2/sangue , Subunidade alfa de Receptor de Interleucina-7/sangue , Ativação Linfocitária/imunologia , Pessoa de Meia-IdadeAssuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Incretinas/efeitos adversos , Meios de Comunicação de Massa , Pancreatopatias/induzido quimicamente , Receptores de Glucagon/efeitos dos fármacos , Ensaios Clínicos como Assunto , Diabetes Mellitus Tipo 2/complicações , Feminino , Receptor do Peptídeo Semelhante ao Glucagon 1 , Humanos , Disseminação de Informação , Masculino , Medição de Risco , TelevisãoAssuntos
Infecções por Coxsackievirus/história , Diabetes Mellitus Tipo 1/história , Anticorpos Antivirais/sangue , Bioquímica/história , Infecções por Coxsackievirus/complicações , Diabetes Mellitus Tipo 1/virologia , Enterovirus Humano B/imunologia , Docentes de Medicina/história , História do Século XX , História do Século XXI , Humanos , MasculinoRESUMO
Insulin-dependent diabetes mellitus (IDDM) is caused by destruction of the insulin-secreting beta-cells of the islets of Langerhans. It is proposed that the disease is caused by nongenetic, probably environmental, factors operating in a genetically susceptible host to initiate a destructive immune process. These environmental factors may operate over a limited period in early childhood to induce the immune process that destroys the islet beta-cell. Thereafter, there is a long prodrome before the onset of clinical diabetes, during which clinical, immune, and metabolic changes can be detected. If these proposals are correct, epidemiological studies should focus on environmental events in early childhood that might induce, or accelerate, the disease process. Moreover, it should be possible to identify, from an early age, changes in the prediabetic period that persist to diagnosis and have predictive value. The variable age of presentation of IDDM may, therefore, reflect different rates of disease progression rather than different ages of exposure to the critical environmental events. Those patients in whom the disease process is slow could present with IDDM as adults, develop diabetes that does not require insulin treatment, or even fail to develop diabetes altogether. These proposed features, if confirmed, would have important implications for the prediction of IDDM and raise the possibility that modulation of the destructive immune process could prevent progression to clinical diabetes.
Assuntos
Diabetes Mellitus Tipo 1/etiologia , Diabetes Mellitus Tipo 2/etiologia , Meio Ambiente , Adolescente , Idade de Início , Autoanticorpos/sangue , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/genética , Doenças em Gêmeos , Humanos , Lactente , Recém-Nascido , Ilhotas Pancreáticas/imunologia , Valor Preditivo dos Testes , Rubéola (Sarampo Alemão)/complicações , Rubéola (Sarampo Alemão)/congênito , Gêmeos Monozigóticos , DesmameRESUMO
The prevalence and features of diabetic retinopathy have been examined in 95 pairs of identical twins, 31 concordant for insulin-dependent diabetes (IDD), 27 discordant for IDD, and 37 concordant for non-insulin-dependent diabetes (NIDD). Optic fundi were examined after pupillary dilatation and retinopathy was classified as nil, background, or severe. In the NIDD twins, 35 of the 37 pairs were in the same category including all but one of the 15 pairs with the same duration of diabetes. However, in insulin-dependent diabetic pairs the situation was quite different; only 21 of 31 pairs were in the same retinopathy category, and of the 10 pairs of co-twins with the same duration of diabetes 5 pairs showed a striking difference for retinopathy. There was no significant difference in the prevalence of retinopathy in the concordant and discordant IDD twin pairs. Diabetic retinopathy was not observed in 32 unaffected co-twins of diabetics. We conclude that genetic factors may be important in the etiology of retinopathy in non-insulin-dependent diabetes but that nongenetic factors must be important in the pathogenesis of retinopathy in insulin-dependent diabetes.
Assuntos
Retinopatia Diabética/epidemiologia , Doenças em Gêmeos , Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/etiologia , Feminino , Humanos , Insulina/farmacologia , Masculino , Gravidez , Gêmeos MonozigóticosRESUMO
Diabetes can retard growth. Growth was studied prospectively in 12 nondiabetic identical twins aged less than 14 yr and in their co-twins with insulin-dependent diabetes mellitus (IDDM) to determine whether changes in growth occur before the onset of IDDM. Seven of the 12 nondiabetic twins subsequently developed IDDM; the remainder are now unlikely to become diabetic. A significantly reduced growth velocity was observed more frequently in the nondiabetic twins (7 of 12) than in their diabetic co-twins (1 of 12; P = 0.03). Of the 7 nondiabetic twins who were prediabetic, 6 had a reduction in growth velocity to below the 3rd percentile before the onset of diabetes compared with 1 of their diabetic co-twins (P = 0.03). However, only 1 of the 5 nondiabetic twins who did not develop diabetes showed a reduction in growth velocity. The nadir of growth in the twins who developed diabetes occurred a mean of 1.2 yr before diagnosis (range 0.3-2.3 yr). All 7 of the prediabetic twins had islet cell antibodies when first seen, and 3 had them before they showed either decreased growth velocity or impaired glucose tolerance. In 4 prediabetic twins, the decreased growth preceded impaired glucose tolerance. The prediabetic twins tested had lower testosterone or estradiol levels at the time they showed decreased growth than their diabetic twins. We conclude that decreased growth velocity is an early sensitive marker of IDDM.
Assuntos
Diabetes Mellitus Tipo 1/fisiopatologia , Transtornos do Crescimento/fisiopatologia , Adolescente , Glicemia/análise , Estatura/fisiologia , Peso Corporal/fisiologia , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/patologia , Doenças em Gêmeos , Estradiol/sangue , Feminino , Teste de Tolerância a Glucose , Transtornos do Crescimento/sangue , Transtornos do Crescimento/etiologia , Humanos , Masculino , Estudos Prospectivos , Testosterona/sangue , Fatores de Tempo , Gêmeos MonozigóticosRESUMO
To evaluate factors influencing the alteration in subsets of T-lymphocytes, we studied 24 pairs of identical twins discordant for insulin-dependent (type I) diabetes mellitus. Subsets were assessed by monoclonal antibodies and a pure preparation of peripheral blood mononuclear cells obtained by centrifugation of heparinized whole blood with a Ficoll/Triosil gradient. In 12 pairs studied within 5 yr of diagnosis, we observed a reduction in the percentage of cells reacting with OKT8 (recognizing the CD8 antigen present on the suppressor/cytotoxic subset) (P less than .05), but a similar level was detected in their nondiabetic cotwins. In 12 pairs studied greater than 5 yr after the diagnosis and in whom the nondiabetic twin is less likely to develop diabetes, the percentage of cells reacting with OKT8 was reduced in both the diabetic (P less than .05) and the nondiabetic (P less than .01) twins. Reductions were also seen with OKT3 (recognizing the CD3 antigen present on the total T-lymphocyte population) and OKT4 (recognizing the CD4 antigen present on the helper/inducer subset), but only in the diabetic twins from the group with longer discordance. We conclude that a reduced percentage of suppressor/cytotoxic cells is associated with type I diabetes, but the reduction appears to be genetically determined. Total T-lymphocytes are also reduced but mainly in the helper/inducer subset and only in diabetic patients of long duration. Such a reduction cannot therefore be primarily genetically determined.
Assuntos
Diabetes Mellitus Tipo 1/genética , Linfócitos T/patologia , Gêmeos Monozigóticos , Gêmeos , Adolescente , Adulto , Anticorpos Monoclonais , Antígenos de Diferenciação de Linfócitos T/análise , Criança , Diabetes Mellitus Tipo 1/sangue , Feminino , Humanos , Contagem de Leucócitos , Ativação Linfocitária , Masculino , Linfócitos T/imunologia , Linfócitos T Citotóxicos/patologia , Linfócitos T Auxiliares-Indutores/patologia , Linfócitos T Reguladores/patologiaRESUMO
HbA(1c), a measure of blood glucose regulation, reflects glucose levels in the preceding months. In diabetes, HbA(1c) levels predict the risk of microvascular complications. The aim of this study was to determine whether genetic factors could influence HbA(1c) levels in normal subjects and type 1 diabetic patients. We performed a classical twin study of HbA(1c) in healthy nondiabetic female twins and 42 monozygotic (MZ) and 47 dizygotic (DZ) pairs. Interclass correlations (r) were higher in MZ (r = 0.77) compared with DZ (r = 0.53) twin pairs, suggesting a substantial genetic effect; this was confirmed by quantitative genetic model fitting. Additive genetic effects (heritability) explained 62% (95% CI 47-75) of population variance in HbA(1c); the remainder was attributable to the influence of unique environment (23% [15-36]) and age (14% [5-28]). Multivariate modeling showed that genetic factors also have a substantial influence on fasting glucose levels (51%). However, HbA(1c) heritability could not be explained by genes in common with fasting glucose. In the patients with type 1 diabetes, HbA(1c) levels were correlated in 33 MZ twins concordant for diabetes (r = 0.68; P < 0.001) but also in 45 MZ twins discordant for the disease (r = 0.52; P < 0.001). These significant correlations for HbA(1c) in both concordant and discordant pairs indicate a diabetes-independent familial effect. Thus, HbA(1c) levels are largely genetically determined and independent of the genes influencing fasting glucose. Even in type 1 diabetes, familial (i.e., diabetes-independent) factors influence protein glycation, implying that familial factors may explain, in part, the risk for microvascular complications, as indicated by high HbA(1c) levels.