A high-fat diet (HFD) is associated with reduced glucose uptake in muscle, but not in adipose tissue. In the present study, we investigated whether a HFD can modulate glucose uptake in adipose tissue by increasing signal transduction through the CAP/Cbl pathway, independently of the PI3-K/Akt pathway. Our results suggest that, in HFD, the differential regulation of insulin-induced glucose uptake between skeletal muscle and adipose tissue may, in part, be a consequence of the CAP/Cbl/C3G pathway, since the expression of CAP and Cbl, and also the activation of this pathway were increased in adipose tissue but not in muscle.
Adipose Tissue/metabolism , Cytoskeletal Proteins/metabolism , Dietary Fats/administration & dosage , Oncogene Protein v-cbl/metabolism , Signal Transduction/physiology , Animals , Cytoskeletal Proteins/genetics , Glucose/metabolism , Insulin/metabolism , Male , Muscle, Skeletal/metabolism , Oncogene Protein v-cbl/genetics , Phosphatidylinositol 3-Kinases/metabolism , Rats , Rats, Wistar
A severe restriction of sodium chloride intake has been associated with insulin resistance and obesity. The molecular mechanisms by which the low salt diet (LS) can induce insulin resistance have not yet been established. The c-jun N-terminal kinase (JNK) activity has been involved in the pathophysiology of obesity and induces insulin resistance by increasing inhibitory IRS-1(ser307) phosphorylation. In this study we have evaluated the regulation of insulin signaling, JNK activation and IRS-1(ser307) phophorylation in liver, muscle and adipose tissue by immunoprecipitation and immunoblotting in rats fed with LS or normal salt diet (NS) during 9 weeks. LS increased body weight, visceral adiposity, blood glucose and plasma insulin levels, induced insulin resistance and did not change blood pressure. In LS rats a decrease in PI3-K/Akt was observed in liver and muscle and an increase in this pathway was seen in adipose tissue. JNK activity and IRS-1(ser307) phosphorylation were higher in insulin-resistant tissues. In summary, the insulin resistance, induced by LS, is tissue-specific and is accompanied by activation of JNK and IRS-1(ser307) phosphorylation. The impairment of the insulin signaling in these tissues, but not in adipose tissue, may lead to increased adiposity and insulin resistance in LS rats.
Insulin/metabolism , JNK Mitogen-Activated Protein Kinases/metabolism , Obesity/etiology , Phosphoproteins/metabolism , Signal Transduction/drug effects , Sodium Chloride, Dietary/administration & dosage , Adipose Tissue/metabolism , Animals , Blood Glucose/analysis , Immunoblotting , Immunoprecipitation , Insulin/blood , Insulin Receptor Substrate Proteins , Insulin Resistance , Liver/metabolism , Male , Muscles/metabolism , Obesity/metabolism , Phosphorylation , Rats , Rats, Wistar
The mechanisms by which diet-induced obesity is associated with insulin resistance are not well established, and no study has until now integrated, in a temporal manner, functional insulin action data with insulin signaling in key insulin-sensitive tissues, including the hypothalamus. In this study, we evaluated the regulation of insulin sensitivity by hyperinsulinemic-euglycemic clamp procedures and insulin signaling, c-jun N-terminal kinase (JNK) activation and insulin receptor substrate (IRS)-1(ser307) phosphorylation in liver, muscle, adipose tissue, and hypothalamus, by immunoprecipitation and immunoblotting, in rats fed on a Western diet (WD) or control diet for 10 or 30 d. WD increased visceral adiposity, serum triacylglycerol, and insulin levels and reduced whole-body glucose use. After 10 d of WD (WD10) there was a decrease in IRS-1/phosphatidylinositol 3-kinase/protein kinase B pathway in hypothalamus and muscle, associated with an attenuation of the anorexigenic effect of insulin in the former and reduced glucose transport in the latter. In WD10, there was an increased glucose transport in adipose tissue in parallel to increased insulin signaling in this tissue. After 30 d of WD, insulin was less effective in suppressing hepatic glucose production, and this was associated with a decrease in insulin signaling in the liver. JNK activity and IRS-1(ser307) phosphorylation were higher in insulin-resistant tissues. In summary, the insulin resistance induced by WD is tissue specific and installs first in hypothalamus and muscle and later in liver, accompanied by activation of JNK and IRS-1(ser307) phosphorylation. The impairment of the insulin signaling in these tissues, but not in adipose tissue, may lead to increased adiposity and insulin resistance in the WD rats.
Diet , Insulin Resistance , Insulin/metabolism , JNK Mitogen-Activated Protein Kinases/metabolism , Phosphoproteins/metabolism , Adipose Tissue/metabolism , Animals , Biological Transport , Blotting, Western , Glucose/metabolism , Glucose Clamp Technique , Hypothalamus/metabolism , Immunoblotting , Immunoprecipitation , Insulin Receptor Substrate Proteins , Liver/metabolism , Male , Muscle, Skeletal/metabolism , Muscles/metabolism , Phosphorylation , Rats , Rats, Wistar , Signal Transduction , Time Factors , Tissue Distribution , Triglycerides/metabolism
A presença de hiperglicemia em pacientes internados por infarto agudo do miocárdio é comum e pode ser conseqüência da descompensação de diabete melito, da liberação de hormônios de estresse ou do uso de drogas que agravam a resistência à insulina. A hiperglicemia durante o infarto agudo do miocárdio é considerada fator de mau prognóstico evolutivo, tanto em diabéticos como em não-diabéticos. Dessa forma, grandes estudos clínicos recomendam que esta seja tratada de forma intensiva, a fim de reduzir a morbidade e a mortalidade de pacientes com infarto agudo do miocárdio. Nesta revisão serão abordados os principais estudos epidemiológicos, a fisiopatologia e o tratamento da hiperglicemia na vigência de infarto agudo do miocárdio.
Humans , Male , Female , Diabetes Mellitus/complications , Diabetes Mellitus/diagnosis , Hyperglycemia/complications , Hyperglycemia/diagnosis , Hyperglycemia/therapy , Myocardial Infarction/complications , Myocardial Infarction/diagnosis , Insulin/therapeutic use
A insulina é um hormônio anabólico com efeitos metabólicos potentes. Os eventos que ocorrem após a ligação da insulina são específicos e estritamente regulados. Definir as etapas que levam à especificidade desse sinal representa um desafio para as pesquisas bioquímicas, todavia podem resultar no desenvolvimento de novas abordagens terapêuticas para pacientes que sofrem de estados de resistência à insulina, especialmente a síndrome metabólica, que compreende o diabetes do tipo 2. O receptor de insulina pertence a uma família de receptores de fatores de crescimento que têm atividade tirosina quinase intrínseca. Após a ligação da insulina, o receptor sofre autofosforilação em múltiplos resíduos de tirosina. Isso resulta na ativação da quinase do receptor e na conseqüente fosforilação em tirosina de uma família de substratos do receptor de insulina (IAS). De forma similar a outros fatores de crescimento, a insulina usa fosforilação e interações proteína-proteína como ferramentas essenciais para transmitir o sinal. Dessa forma, o sinal é transmitido do receptor ao efetor final, promovendo a translocação de vesículas contendo transportadores de glicose (GLUT4) do conteúdo intracelular para a membrana plasmática, a ativação da síntese de glicogênio e de proteínas, e a transcrição de genes específicos.
Humans , Male , Female , Protein-Tyrosine Kinases , Receptor, Insulin/analysis , Insulin Resistance/physiology , Diabetes Mellitus/physiopathology , Obesity/complications , Obesity/diagnosis , Metabolic Syndrome/complications , Metabolic Syndrome/diagnosis
Estudos epidemiológicos demonstram forte associação entre resistência à insulina, hipertensão e morbidade cardiovascular. A insulina, além de seus efeitos metabólicos, exerce efeitos cardiovasculares mediados pelo sistema nervoso simpático e pela via do óxido nítrico (NO). Em situações normais, a insulina ativa a produção de NO em células endoteliais através de um mecanismo dependente da fosfatidilinositol (PI) 3-quinase, com ativação da Akt e subseqüente fosforilação da óxido nítrico sintase endotelial (eNOS ou NOS3) em resíduos de serina, levando ao aumento da produção local de NO. As ações da insulina no sistema cardiovascular estão reduzidas em diversos estados de resistência à insulina, como o diabetes tipo 2, e a hipótese mais aceita atualmente para explicar a associação observada entre hipertensão arterial e resistência à insulina é a disfunção endotelial gerada por um bloqueio seletivo na via da PI3-quinase/Akt/eNOS no endotélio
Humans , Mice , Rats , Diabetes Mellitus , Cardiovascular Diseases/physiopathology , Hypertension/physiopathology , Insulin Resistance , Risk Factors
Acredita-se atualmente que o diabetes tipo 2 ocorra em indivíduos geneticamente predispostos e expostos a uma série de influências ambientais, que precipitam o início da doença. O padrão de herança do diabetes melito tipo 2 é complexo e provavelmente poligênico. Apesar dos esforços, apenas alguns genes têm sido consistentemente relacionados a maior suscetibilidade à doença
Humans , Diabetes Mellitus, Type 2 , Protein-Tyrosine Kinases , Receptor, Insulin/physiology , Insulin Resistance/physiology , Disease Susceptibility , Genome, Human , Genetics/trends
