RESUMO
La diabetes mellitus (DM) es una enfermedad heterogénea que presenta fenotipos clínicos diversos, todos con hiperglucemia. Históricamente se han utilizado cuatro factores para identificar esta diversidad: la edad de inicio, la gravedad de la enfermedad o grado de pérdida de la función de la célula beta, el grado de resistencia a la insulina y la presencia de autoanticuerpos asociados a la enfermedad. Actualmente, los parámetros empleados para clasificar los diferentes tipos de DM dificultan el diagnóstico y tratamiento de los pacientes. Las distintas presentaciones clínicas requieren una clasificación diagnóstica más eficaz para un abordaje terapéutico más preciso, valiéndose del avance de la inmunogenética y la bioquímica clínica. Esta guía está orientada a clasificar con precisión las presentaciones clínicas que a menudo generan incertidumbre dentro de los dos tipos principales de DM.
Diabetes mellitus (DM) is a heterogeneous disease, with diverse clinical phenotypes, all with hyperglycemia. Historically, four factors have been used to identify this diversity: the age at onset, the severity of the disease, that is, the degree of loss of beta cell function and insulin resistance, and the presence of circulating autoantibodies. Currently, the parameters used to classify the different types of DM make it difficult to diagnose and treat patients. The different clinical manifestations require an accurate diagnosis to achieve an effective therapeutic approach through the use of immunogenetics and clinical biochemistry. This practical guide aims to accurately classify the often uncertain clinical presentations within the two main types of diabetes.
Assuntos
Diabetes Mellitus , Autoanticorpos , Autoimunidade , GenéticaRESUMO
La diabetes mellitus (DM) es una enfermedad heterogénea que presenta fenotipos clínicos diversos, todos con hiperglucemia. Históricamente se han utilizado cuatro factores para identificar esta diversidad: la edad de inicio, la gravedad de la enfermedad o grado de pérdida de la función de la célula beta, el grado de resistencia a la insulina y la presencia de autoanticuerpos asociados a la enfermedad. Actualmente, los parámetros empleados para clasificar los diferentes tipos de DM dificultan el diagnóstico y tratamiento de los pacientes. Las distintas presentaciones clínicas requieren una clasificación diagnóstica más eficaz para un abordaje terapéutico más preciso, valiéndose del avance de la inmunogenética y la bioquímica clínica. Esta guía está orientada a clasificar con precisión las presentaciones clínicas que a menudo generan incertidumbre dentro de los dos tipos principales de DM.
Diabetes mellitus (DM) is a heterogeneous disease, with diverse clinical phenotypes, all with hyperglycemia. Historically, four factors have been used to identify this diversity: the age at onset, the severity of the disease, that is, the degree of loss of beta cell function and insulin resistance, and the presence of circulating autoantibodies. Currently, the parameters used to classify the different types of DM make it difficult to diagnose and treat patients. The different clinical manifestations require an accurate diagnosis to achieve an effective therapeutic approach through the use of immunogenetics and clinical biochemistry. This practical guide aims to accurately classify the often uncertain clinical presentations within the two main types of diabetes.
Assuntos
GenéticaRESUMO
AIMS: Posttranslational modifications of histones and transcription factors regulate gene expression and are implicated in beta-cell failure and diabetes. We have recently shown that preserving H3K27 and H3K4 methylation using the lysine demethylase inhibitor GSK-J4 reduces cytokine-induced destruction of beta-cells and improves beta-cell function. Here, we investigate the therapeutic potential of GSK-J4 to prevent diabetes development and examine the importance of H3K4 methylation for islet function. MATERIALS AND METHODS: We used two mouse models of diabetes to investigate the therapeutic potential of GSK-J4. To clarify the importance of H3K4 methylation, we characterized a mouse strain with knockout (KO) of the H3K4 demethylase KDM5B. RESULTS: GSK-J4 administration failed to prevent the development of experimental diabetes induced by multiple low-dose streptozotocin or adoptive transfer of splenocytes from acutely diabetic NOD to NODscid mice. KDM5B-KO mice were growth retarded with altered body composition, had low IGF-1 levels, and exhibited reduced insulin secretion. Interestingly, despite secreting less insulin, KDM5B-KO mice were able to maintain normoglycemia following oral glucose tolerance test, likely via improved insulin sensitivity, as suggested by insulin tolerance testing and phosphorylation of proteins belonging to the insulin signaling pathway. When challenged with high-fat diet, KDM5B-deficient mice displayed similar weight gain and insulin sensitivity as wild-type mice. CONCLUSION: Our results show a novel role of KDM5B in metabolism, as KDM5B-KO mice display growth retardation and improved insulin sensitivity.
Assuntos
Metabolismo dos Carboidratos/genética , Proteínas de Ligação a DNA/fisiologia , Glucose/metabolismo , Células Secretoras de Insulina/fisiologia , Ilhotas Pancreáticas/fisiologia , Histona Desmetilases com o Domínio Jumonji/fisiologia , Animais , Proteínas de Ligação a DNA/genética , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Transtornos do Crescimento/genética , Transtornos do Crescimento/metabolismo , Homeostase/genética , Resistência à Insulina/genética , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Histona Desmetilases com o Domínio Jumonji/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , EstreptozocinaRESUMO
It is well established the link between inflammation and the development of insulin resistance and pathogenesis of type 2 diabetes. Type 1 diabetes is an autoimmune disease characterized by the destruction of insulin-producing pancreatic ß cells mediated by autoreactive T lymphocytes and pro-inflammatory agents. Therefore, developing new strategies to efficiently control dysregulated inflammation could have substantial benefits in the treatment of diabetes. Recently, a novel population of non-tumorigenic pluripotent stem cells, named multilineage-differentiating stress-enduring (Muse) cells, was discovered. Muse cells secrete significant amounts of TGF-ß1, a key cytokine governing down-modulation of T lymphocytes and macrophages. In this chapter, we discuss the immunomodulatory properties of Muse cells as well as the molecular mechanism of TGF-ß1 as mediator of Muse cell action. We also describe the role of certain cytokines/growth factors highly expressed in Muse cells as potential mediators of their effects. Finally, we provide evidence of the beneficial effects of adipose tissue-derived Muse cells in an experimental mice model of type 1 diabetes.