RESUMEN
The insulin receptor substrate (IRS) proteins are a family of cytoplasmic proteins that integrate and coordinate the transmission of signals from the extracellular to the intracellular environment via transmembrane receptors, thus regulating cell growth, metabolism, survival and proliferation. The PI3K/AKT/mTOR and MAPK signaling pathways are the best-characterized downstream signaling pathways activated by IRS signaling (canonical pathways). However, novel signaling axes involving IRS proteins (noncanonical pathways) have recently been identified in solid tumor and hematologic neoplasm models. Insulin receptor substrate-1 (IRS1) and insulin receptor substrate-2 (IRS2) are the best-characterized IRS proteins in hematologic-related processes. IRS2 binds to important cellular receptors involved in normal hematopoiesis (EPOR, MPL and IGF1R). Moreover, the identification of IRS1/ABL1 and IRS2/JAK2V617F interactions and their functional consequences has opened a new frontier for investigating the roles of the IRS protein family in malignant hematopoiesis. Insulin receptor substrate-4 (IRS4) is absent in normal hematopoietic tissues but may be expressed under abnormal conditions. Moreover, insulin receptor substrate-5 (DOK4) and insulin receptor substrate-6 (DOK5) are linked to lymphocyte regulation. An improved understanding of the signaling pathways mediated by IRS proteins in hematopoiesis-related processes, along with the increased development of agonists and antagonists of these signaling axes, may generate new therapeutic approaches for hematological diseases. The scope of this review is to recapitulate and review the evidence for the functions of IRS proteins in normal and malignant hematopoiesis.
Asunto(s)
Hematopoyesis/fisiología , Proteínas Sustrato del Receptor de Insulina/metabolismo , Leucemia Linfoide/metabolismo , Leucemia Mieloide/metabolismo , Transducción de Señal/fisiología , Humanos , Proteínas Sustrato del Receptor de Insulina/fisiología , Leucemia Linfoide/fisiopatología , Leucemia Mieloide/fisiopatologíaRESUMEN
The insulin receptor substrate (IRS) proteins are a family of cytoplasmic proteins that integrate and coordinate the transmission of signals from the extracellular to the intracellular environment via transmembrane receptors, thus regulating cell growth, metabolism, survival and proliferation. The PI3K/AKT/mTOR and MAPK signaling pathways are the best-characterized downstream signaling pathways activated by IRS signaling (canonical pathways). However, novel signaling axes involving IRS proteins (noncanonical pathways) have recently been identified in solid tumor and hematologic neoplasm models. Insulin receptor substrate-1 (IRS1) and insulin receptor substrate-2 (IRS2) are the best-characterized IRS proteins in hematologic-related processes. IRS2 binds to important cellular receptors involved in normal hematopoiesis (EPOR, MPL and IGF1R). Moreover, the identification of IRS1/ABL1 and IRS2/JAK2V617F interactions and their functional consequences has opened a new frontier for investigating the roles of the IRS protein family in malignant hematopoiesis. Insulin receptor substrate-4 (IRS4) is absent in normal hematopoietic tissues but may be expressed under abnormal conditions. Moreover, insulin receptor substrate-5 (DOK4) and insulin receptor substrate-6 (DOK5) are linked to lymphocyte regulation. An improved understanding of the signaling pathways mediated by IRS proteins in hematopoiesis-related processes, along with the increased development of agonists and antagonists of these signaling axes, may generate new therapeutic approaches for hematological diseases. The scope of this review is to recapitulate and review the evidence for the functions of IRS proteins in normal and malignant hematopoiesis.
Asunto(s)
Humanos , Transducción de Señal/fisiología , Leucemia Linfoide/metabolismo , Leucemia Mieloide/metabolismo , Proteínas Sustrato del Receptor de Insulina/metabolismo , Hematopoyesis/fisiología , Leucemia Linfoide/fisiopatología , Leucemia Mieloide/fisiopatología , Proteínas Sustrato del Receptor de Insulina/fisiologíaRESUMEN
Alzheimer's disease (AD) and diabetes are currently considered among the top threats to human health worldwide. Intriguingly, a connection between these diseases has been established during the past decade, since insulin resistance, a hallmark of type 2 diabetes, also develops in Alzheimer brains. In this article, the molecular and cellular mechanisms underlying defective brain insulin signaling in AD are discussed, with emphasis on evidence that Alzheimer's and diabetes share common inflammatory signaling pathways. I put forward here a hypothesis on how a cross-talk between peripheral tissues and the brain might influence the development of AD, and highlight important unanswered questions in the field. Furthermore, I discuss a rational basis for the use of antidiabetic agents as novel and potentially effective therapeutics in AD.
Asunto(s)
Enfermedad de Alzheimer/etiología , Enfermedad de Alzheimer/fisiopatología , Resistencia a la Insulina/fisiología , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/fisiología , Péptidos beta-Amiloides/toxicidad , Animales , Encéfalo/efectos de los fármacos , Encéfalo/fisiopatología , Diabetes Mellitus Tipo 2/etiología , Diabetes Mellitus Tipo 2/fisiopatología , Humanos , Proteínas Sustrato del Receptor de Insulina/fisiología , Factor I del Crecimiento Similar a la Insulina/fisiología , Modelos Neurológicos , Neurotoxinas/metabolismo , Neurotoxinas/toxicidad , Estrés Oxidativo , Receptor de Insulina/efectos de los fármacos , Receptor de Insulina/fisiología , Transducción de Señal/efectos de los fármacos , Investigación Biomédica TraslacionalRESUMEN
Retinopathy, a common complication of diabetes, is characterized by an unbalanced production of nitric oxide (NO), a process regulated by nitric oxide synthase (NOS). We hypothesized that retinopathy might stem from changes in the insulin receptor substrate (IRS)/PI3K/AKT pathway and/or expression of NOS isoforms. Thus, we analysed the morphology and apoptosis index in retinas of obese rats in whom insulin resistance had been induced by a high-fat diet (HFD). Immunoblotting analysis revealed that the retinal tissue of HFD rats had lower levels of AKT(1) , eNOS and nNOS protein than those of samples taken from control animals. Furthermore, immunohistochemical analyses indicated higher levels of iNOS and 4-hydroxynonenal and a larger number of apoptotic nuclei in HFD rats. Finally, both the inner and outer retinal layers of HFD rats were thinner than those in their control counterparts. When considered alongside previous results, these patterns suggest two major ways in which HFD might impact animals: direct activity of ingested fatty acids and/or via insulin-resistance-induced changes in intracellular pathways. We discuss these possibilities in further detail and advocate the use of this animal model for further understanding relationships between retinopathy, metabolic syndrome and type 2 diabetes.
Asunto(s)
Grasas de la Dieta/toxicidad , Proteínas del Ojo/fisiología , Obesidad/fisiopatología , Proteínas Proto-Oncogénicas c-akt/fisiología , Degeneración Retiniana/etiología , Animales , Apoptosis , Astrocitos/patología , Glucemia/análisis , Retinopatía Diabética , Modelos Animales de Enfermedad , Ácidos Grasos/sangre , Proteínas Sustrato del Receptor de Insulina/fisiología , Resistencia a la Insulina , Peroxidación de Lípido , Lípidos/sangre , Hígado/patología , Masculino , Óxido Nítrico Sintasa de Tipo I/fisiología , Óxido Nítrico Sintasa de Tipo III/fisiología , Obesidad/sangre , Obesidad/complicaciones , Fosfatidilinositol 3-Quinasas/fisiología , Ratas , Ratas Wistar , Retina/metabolismo , Retina/patología , Degeneración Retiniana/sangre , Degeneración Retiniana/fisiopatología , Transducción de SeñalRESUMEN
Insulin receptor substrate 2 (IRS2) is an adaptor protein that associates with the receptor of erythropoietin, insulin-like growth factor 1 and thrombopoietin; however, its role is not known in myelodysplasia. We, herein, report a significantly lower IRS2 expression in MDS cells, compared to normal cells. IRS2 expression was reduced in high-risk, compared to low-risk disease, and positively correlated with neutrophil and platelet counts. IRS2 was upregulated during erythroid differentiation of CD34(+) cells from normal donors and low-risk MDS patients and also during erythroid, granulocytic and megakaryocytic differentiation in cell lines. These results suggest that defective IRS2 expression plays a role in the impaired hematopoietic cell differentiation in MDS.
Asunto(s)
Hematopoyesis/genética , Células Madre Hematopoyéticas/fisiología , Proteínas Sustrato del Receptor de Insulina/genética , Proteínas Sustrato del Receptor de Insulina/fisiología , Síndromes Mielodisplásicos/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Diferenciación Celular/genética , Línea Celular Tumoral , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Regulación hacia Abajo/genética , Regulación Leucémica de la Expresión Génica , Hematopoyesis/fisiología , Células Madre Hematopoyéticas/metabolismo , Humanos , Leucemia/etiología , Leucemia/genética , Leucemia/patología , Persona de Mediana Edad , Síndromes Mielodisplásicos/fisiopatología , Factores de Riesgo , Adulto JovenRESUMEN
In Yucatán, 52% of patients with type 2 diabetes (DT2) present secondary failure to treatment associated with sulphonylurea and metformin. A possible explanation may be due to polymorphisms in the genes IRS1, CAPN10, PPARG2, which are involved in pancreatic beta cell dysfunction and a poor response to the action of insulin. The association of the polymorphisms Gly972Arg, SNP43, and Pro12Ala, of the genes IRS1, CAPN10, PPARG2, with the risk of failure to sulphonylurea and metformin therapies was determinated in patients with DT2 in Yucatán, México. One hundred and thirty and two subjects with DT2 were classified in groups of responders (HbA1c < 8%) and non-responders (HbA1c > 8%) to the treatment, according to the control of hyperglucemia with sulphonylurea and metformin. Demographic, anthropometric and metabolic data were obtained from each subject. The polymorphisms were identified by means of DNA analysis by PCR/RFLP and PCR/OAL. Genotypic and allelic frequencies and the Hardy-Weinberg equilibrium were determined. Statistical analyses consisted of X2 and multiple logistic regression tests (Epi-Info 2000 and SPSS version 12). Obese subjects carrying the genotype AA SNP43 showed 4.69 times more risk of failure to respond to treatment (p = 0.027), when compared with subjects sharing GA genotype: X2 (OR = 4.69, IC: 1.15-20.59) and multiple logistic regression, p = 0.048, (OR = 3.72, IC: 1.009-13.718). The interaction between genotype AA and the BMI > 27 showed also a significant difference (p = 0.009). The findings suggest the fact that polymorphism SNP43 may influence the response to treatment with sulphonylurea and metformin, the expression being dependent on obesity.