CONVICÇÕES DE SAÚDE DE PAIS DE CRIANÇAS PORTADORAS DE DIABETES MELLITUS TIPO 1

O Diabetes Mellitus tipo 1 geralmente ocorre na infância ou adolescência e repercute de forma dramática na vida dos pais. A família é fundamental no tratamento do paciente: representa o alicerce que influenciará na aceitação ou não da enfermidade por parte do portador. Por isso, os objetivos deste estudo foram descrever as convicções de saúde de pais de crianças portadoras de diabetes mellitus tipo 1 e compreender mudanças comportamentais e psíquicas que possam influenciar na conduta em relação ao tratamento. Investigou-se 13 pessoas, pais de crianças de 11 meses a 10 anos portadoras de Diabetes Mellitus Tipo 1, por intermédio de uma entrevista para levantamento e descrição de fatores de convicção de saúde. Os dados foram avaliados com base em um modelo de “convicção de saúde”. Esse modelo avaliou: impacto do diagnóstico, suscetibilidade, severidade, benefícios, barreiras, eficácia própria e expectativa de futuro de cada um dos pais. Os resultados mostraram que os pais experimentam dificuldades, medos e inseguranças, pela doença do filho. Ao relatarem as situações vividas desde o diagnóstico até o momento atual, em todas as etapas, os pais revelam intenso sofrimento. Eles são constantemente invadidos por medo de perda tanto no presente como no futuro em função das complicações da doença. A partir desses resultados recomenda-se que os pais recebam atendimento de uma equipe multidisciplinar com conhecimento específico e com a finalidade de informar sobre a doença e aplacar os medos e inseguranças que criam obstáculos para a adesão ao tratamento. Espera-se com este tipo de atendimento melhorar e a qualidade de vida do paciente e de sua família.

CONVICÇÕES DE SAÚDE DE PAIS DE CRIANÇAS PORTADORAS DE DIABETES MELLITUS TIPO 1

O Diabetes Mellitus tipo 1 geralmente ocorre na infância ou adolescência e repercute de forma dramática na vida dos pais. A família é fundamental no tratamento do paciente: representa o alicerce que influenciará na aceitação ou não da enfermidade por parte do portador. Por isso, os objetivos deste estudo foram descrever as convicções de saúde de pais de crianças portadoras de diabetes mellitus tipo 1 e compreender mudanças comportamentais e psíquicas que possam influenciar na conduta em relação ao tratamento. Investigou-se 13 pessoas, pais de crianças de 11 meses a 10 anos portadoras de Diabetes Mellitus Tipo 1, por intermédio de uma entrevista para levantamento e descrição de fatores de convicção de saúde. Os dados foram avaliados com base em um modelo de “convicção de saúde”. Esse modelo avaliou: impacto do diagnóstico, suscetibilidade, severidade, benefícios, barreiras, eficácia própria e expectativa de futuro de cada um dos pais. Os resultados mostraram que os pais experimentam dificuldades, medos e inseguranças, pela doença do filho. Ao relatarem as situações vividas desde o diagnóstico até o momento atual, em todas as etapas, os pais revelam intenso sofrimento. Eles são constantemente invadidos por medo de perda tanto no presente como no futuro em função das complicações da doença. A partir desses resultados recomenda-se que os pais recebam atendimento de uma equipe multidisciplinar com conhecimento específico e com a finalidade de informar sobre a doença e aplacar os medos e inseguranças que criam obstáculos para a adesão ao tratamento. Espera-se com este tipo de atendimento melhorar e a qualidade de vida do paciente e de sua família.

Major histocompatibility complex class I-restricted T cells are required for all but the end stages of diabetes development in nonobese diabetic mice and use a prevalent T cell receptor α chain gene rearrangement

Nonobese diabetic (NOD) mice develop insulin-dependent diabetes mellitus due to autoimmune T lymphocyte-mediated destruction of pancreatic β cells. Although both major histocompatibility complex class I-restricted CD8+ and class II-restricted CD4+ T cell subsets are required, the specific role each subset plays in the pathogenic process is still unclear. Here we show that class I-dependent T cells are required for all but the terminal stages of autoimmune diabetes development. To characterize the diabetogenic CD8+ T cells responsible, we isolated and propagated in vitro CD8+ T cells from the earliest insulitic lesions of NOD mice. They were cytotoxic to NOD islet cells, restricted to H-2Kd, and showed a diverse T cell receptor β chain repertoire. In contrast, their α chain repertoire was more restricted, with a recurrent amino acid sequence motif in the complementarity-determining region 3 loop and a prevalence of Vα17 family members frequently joined to the Jα42 gene segment. These results suggest that a number of the CD8+ T cells participating in the initial phase of autoimmune β cell destruction recognize a common structural component of Kd/peptide complexes on pancreatic β cells, possibly a single peptide.

The maturity-onset diabetes of the young (MODY1) transcription factor HNF4α regulates expression of genes required for glucose transport and metabolism

Hepatocyte nuclear factor 4α (HNF4α) plays a critical role in regulating the expression of many genes essential for normal functioning of liver, gut, kidney, and pancreatic islets. A nonsense mutation (Q268X) in exon 7 of the HNF4α gene is responsible for an autosomal dominant, early-onset form of non-insulin-dependent diabetes mellitus (maturity-onset diabetes of the young; gene named MODY1). Although this mutation is predicted to delete 187 C-terminal amino acids of the HNF4α protein the molecular mechanism by which it causes diabetes is unknown. To address this, we first studied the functional properties of the MODY1 mutant protein. We show that it has lost its transcriptional transactivation activity, fails to dimerize and bind DNA, implying that the MODY1 phenotype is because of a loss of HNF4α function. The effect of loss of function on HNF4α target gene expression was investigated further in embryonic stem cells, which are amenable to genetic manipulation and can be induced to form visceral endoderm. Because the visceral endoderm shares many properties with the liver and pancreatic β-cells, including expression of genes for glucose transport and metabolism, it offers an ideal system to investigate HNF4-dependent gene regulation in glucose homeostasis. By exploiting this system we have identified several genes encoding components of the glucose-dependent insulin secretion pathway whose expression is dependent upon HNF4α. These include glucose transporter 2, and the glycolytic enzymes aldolase B and glyceraldehyde-3-phosphate dehydrogenase, and liver pyruvate kinase. In addition we have found that expression of the fatty acid binding proteins and cellular retinol binding protein also are down-regulated in the absence of HNF4α. These data provide direct evidence that HNF4α is critical for regulating glucose transport and glycolysis and in doing so is crucial for maintaining glucose homeostasis.

Mechanisms of β cell death in diabetes: A minor role for CD95

Insulin-dependent diabetes mellitus is an autoimmune disease, under polygenic control, manifested only when >90% of the insulin-producing β cells are destroyed. Although the disease is T cell mediated, the demise of the β cell results from a number of different insults from the immune system. It has been proposed that foremost amongst these effector mechanisms is CD95 ligand-induced β cell death. Using the nonobese diabetic lpr mouse as a model system, we have found, to the contrary, that CD95 plays only a minor role in the death of β cells. Islet grafts from nonobese diabetic mice that carry the lpr mutation and therefore lack CD95 were protected only marginally from immune attack when grafted into diabetic mice. An explanation to reconcile these differing results is provided.

Correction of obesity and diabetes in genetically obese mice by leptin gene therapy

The ob/ob mouse is genetically deficient in leptin and exhibits both an obese and a mild non-insulin-dependent diabetic phenotype. To test the hypothesis that correction of the obese phenotype by leptin gene therapy will lead to the spontaneous correction of the diabetic phenotype, the ob/ob mouse was treated with a recombinant adenovirus expressing the mouse leptin cDNA. Treatment resulted in dramatic reductions in both food intake and body weight, as well as the normalization of serum insulin levels and glucose tolerance. The subsequent diminishment in serum leptin levels resulted in the rapid resumption of food intake and a gradual gain of body weight, which correlated with the gradual return of hyperinsulinemia and insulin resistance. These results not only demonstrated that the obese and diabetic phenotypes in the adult ob/ob mice are corrected by leptin gene treatment but also provide confirming evidence that body weight control may be critical in the long-term management of non-insulin-dependent diabetes mellitus in obese patients.

Induction of resistance to diabetes in non-obese diabetic mice by targeting CD44 with a specific monoclonal antibody

Inflammatory destruction of insulin-producing β cells in the pancreatic islets is the hallmark of insulin-dependent diabetes mellitus, a spontaneous autoimmune disease of non-obese diabetic mice resembling human juvenile (type I) diabetes. Histochemical analysis of diabetic pancreata revealed that mononuclear cells infiltrating the islets and causing autoimmune insulitis, as well as local islet cells, express the CD44 receptor; hyaluronic acid, the principal ligand of CD44, is detected in the islet periphery and islet endothelium. Injection of anti-CD44 mAb 1 hr before cell transfer of diabetogenic splenocytes and subsequently on alternate days for 4 weeks induced considerable resistance to diabetes in recipient mice, reflected by reduced insulitis. Contact sensitivity to oxazolone was not influenced by this treatment. A similar antidiabetic effect was observed even when the anti-CD44 mAb administration was initiated at the time of disease onset: i.e., 4–7 weeks after cell transfer. Administration of the enzyme hyaluronidase also induced appreciable resistance to insulin-dependent diabetes mellitus, suggesting that the CD44–hyaluronic acid interaction is involved in the development of the disease. These findings demonstrate that CD44-positive inflammatory cells may be a potential therapeutic target in insulin-dependent diabetes.

Will new diagnostic criteria for diabetes mellitus change phenotype of patients with diabetes? Reanalysis of European epidemiological data

Objective: To evaluate the impact of the revised diagnostic criteria for diabetes mellitus adopted by the American Diabetes Association on prevalence of diabetes and on classification of patients. For epidemiological purposes the American criteria use a fasting plasma glucose concentration ⩾7.0 mmol/l in contrast with the current World Health Organisation criteria of 2 hour glucose concentration ⩾11.1 mmol/l.

Identification and modulation of a naturally processed T cell epitope from the diabetes-associated autoantigen human glutamic acid decarboxylase 65 (hGAD65)

T cell recognition of autoantigens is critical to progressive immune-mediated destruction of islet cells, which leads to autoimmune diabetes. We identified a naturally presented autoantigen from the human islet antigen glutamic acid decarboxylase, 65-kDa isoform (GAD65), by using a combination of chromatography and mass spectrometry of peptides bound by the type I diabetes (insulin-dependent diabetes mellitus, IDDM)-associated HLA-DR4 molecule. Peptides encompassing this epitope-stimulated GAD65-specific T cells from diabetic patients and a DR4-positive individual at high risk for developing IDDM. T cell responses were antagonized by altered peptide ligands containing single amino acid modifications. This direct identification and manipulation of GAD65 epitope recognition provides an approach toward dissection of the complex CD4+ T cell response in IDDM.