RESUMO
BACKGROUND: Angiotensin II (AII) has been shown to contribute to the pathogenesis of hypertension and insulin resistance. In addition, the administration of selective AII type 1 receptor blockers has been shown to improve insulin sensitivity. However, only a few studies have addressed the molecular mechanisms involved in this association. Furthermore, in a previous study we illustrated that obese Zucker rats (OZR) present increased serine 994 (Ser994) phosphorylation of hepatic insulin receptor, and this event seems to be implicated in the regulation of the intrinsic IRK in this model of insulin resistance. OBJECTIVE AND DESIGN: We examined the effects of chronic treatment with irbesartan (50 mg/kg a day for 6 months) on the hepatic insulin signaling system of OZR. METHODS: The extent of phosphorylation of several components of the insulin signaling system was assessed by immunoprecipitation, followed by immunoblotting with phosphospecific antibodies. In addition, liver AII levels and fat deposits were determined by immunohistochemistry and Oil red O, respectively. RESULTS: OZR displayed a marked attenuation in the in-vivo phosphorylation of several components of the insulin signaling pathways in the liver, together with significantly higher hepatic AII levels and hepatic steatosis when compared with lean Zucker rats. We found that in the livers of OZR long-term administration of irbesartan is associated with: (i) increased insulin-stimulated insulin receptor tyrosine phosphorylation; (ii) decreased insulin receptor Ser994 phosphorylation; (iii) augmented insulin receptor substrate (IRS) 1 and 2 abundance and tyrosine phosphorylation; (iv) augmented association between IRS and the p85 regulatory subunit of phosphatidylinositol 3-kinase; (v) increased insulin-induced Akt phosphorylation; and (vi) decreased hepatic steatosis. CONCLUSION: The present study provides substantial information that demonstrates that long-term selective AII blockade by irbesartan improves insulin signaling and is associated with decreased insulin receptor Ser994 phosphorylation in the liver of a representative animal model of the human metabolic syndrome.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Anti-Hipertensivos/farmacologia , Compostos de Bifenilo/farmacologia , Resistência à Insulina , Obesidade/metabolismo , Obesidade/fisiopatologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tetrazóis/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Análise de Variância , Angiotensina II/efeitos dos fármacos , Angiotensina II/metabolismo , Animais , Biomarcadores/sangue , Biomarcadores/urina , Pressão Sanguínea , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Fígado Gorduroso/metabolismo , Fígado Gorduroso/fisiopatologia , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Proteínas Substratos do Receptor de Insulina , Peptídeos e Proteínas de Sinalização Intracelular/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Irbesartana , Masculino , Proteína Quinase 3 Ativada por Mitógeno/efeitos dos fármacos , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fosfatidilinositol 3-Quinases/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Fosfoproteínas/efeitos dos fármacos , Fosfoproteínas/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Ratos , Ratos Zucker , Receptor de Insulina/efeitos dos fármacos , Receptor de Insulina/metabolismo , Proteínas Adaptadoras da Sinalização Shc , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de SrcRESUMO
Growth hormone (GH) is an important modulator of insulin sensitivity. Multiple mechanisms appear to be involved in this modulatory effect. GH does not interact directly with the insulin receptor (IR), but conditions of GH excess are associated in general with hyperinsulinemia that induces a reduction of IR levels and impairment of its kinase activity. Several post-receptor events are shared between GH and insulin. This signaling crosstalk could be involved in the diabetogenic effects of GH. The utilization of animal models of GH excess, deficiency or resistance provided evidence that the signaling pathway leading to stimulation of the phosphatidylinositol 3-kinase (PI3K)/Akt cascade is an important site of regulation, and pointed to the liver as the major site of GH-induced insulin resistance. In skeletal muscle, GH-induced insulin resistance might involve an increase in the amount of the p85 subunit of PI3K that plays a negative role in insulin signalling. GH also reduces insulin sensitivity by enhancing events that negatively modulate insulin signaling such as stimulation of serine phosphorylation of IRS-1, which prevents its recruitment to the IR and induction of the suppressor of cytokine signalling (SOCS)-1 and SOCS-3 which modulate the signalling potential of the IRS proteins. In addition, GH has been shown to decrease the expression of the insulin-sensitizing adipo-cytokines adiponectin and visfatin. Finally, genetic manipulation of mice indicated that whereas GH plays a major role in reducing insulin sensitivity, circulating IGF-I also participates in the control of insulin sensitivity and plays an important role in the hormonal balance between GH and insulin.
Assuntos
Hormônio do Crescimento/fisiologia , Resistência à Insulina , Insulina/fisiologia , Transdução de Sinais/fisiologia , Animais , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Receptor de Insulina/metabolismoRESUMO
In this study, we analyzed the effects of long-term (14 months) caloric restriction (CR) on the first steps of the insulin signaling system in skeletal muscle of normal mice. CR induced a significant decrease in serum insulin and glucose levels, indicating an enhancement of insulin sensitivity. CR reduced the in vivo insulin-induced phosphorylation of the insulin receptor substrate (IRS)-1 by 27%, but this difference was not significant (p =.298). CR reduced insulin receptor (IR) abundance by 34% from the ad libitum values, but this difference did not reach significance (p =.246). The abundance of the p85 regulatory subunit of PI3K and glucose transporter 4 was unaltered after CR. However, IRS-1 abundance was significantly increased by 42% in muscle of mice exposed to CR. These findings indicate that the CR-induced improvement of insulin action in mice is not related to changes in glucose transporter 4, the p85 regulatory subunit of PI3K, or IR abundance in skeletal muscle but might be related to an increase in IRS-1 abundance in this tissue.
Assuntos
Restrição Calórica , Insulina/fisiologia , Músculo Esquelético/fisiologia , Transdução de Sinais/fisiologia , Animais , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Fosforilação , Fatores de Tempo , Tirosina/metabolismoRESUMO
The in vivo status of the proximal components of the insulin signaling system was investigated in skeletal muscle of Ames (Prop1df/Prop1df) dwarf mice. The insulin-stimulated phosphorylation of the insulin receptor (IR) was reduced by 55% in Ames dwarf mice, while IR receptor protein content was not altered. Insulin-stimulated phosphorylation of IRS-1 and IRS-2 were decreased by 79 and 51%, respectively, while IRS-1 and IRS-2 protein levels were decreased by 66 and 43%. In addition, insulin-stimulated association of IRS-1 and IRS-2 with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase was significantly reduced (by 80 and 41%, respectively), whereas insulin-stimulated PI 3-kinase activity was reduced by 66%. However, insulin-stimulated phosphorylation of Akt was slightly reduced (by 20%), suggesting that the attenuation of insulin signaling downstream PI 3-kinase may involve other signaling molecules. Our current results demonstrate that the Prop1 mutation decreases high dose insulin responses in skeletal muscle. This alteration is remarkable because these animals are hypersensitive to insulin and display an augmented response to insulin in liver at the same signaling steps. Reduced response to insulin in skeletal muscle could be important for the control of glucose homeostasis in these animals and could have implications in their extended longevity.