Modulation of IR/PTP1B interaction and downstream signaling in insulin sensitive tissues of MSG-rats

Hirata, Aparecida Emiko; Alvarez-Rojas, Fernanda; Carvalheira, José Barreto Campello; Carvalho, Carla Roberta de Oliveira; Dolnikoff, Miriam Sterman; Saad, Mário José Abdalla

doi:10.1016/s0024-3205(03)00477-6

Cited by 57 publications

(41 citation statements)

References 21 publications

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“…Diet-induced obesity (DIO) is an experimental model associated with insulin resistance at a molecular level in liver and muscle, but not in adipose tissue [5,6]. On the other hand, mice with fat-specific disruption of the gene encoding the IR have low fat mass and are protected against DIO and glucose intolerance [7], suggesting that in some situations, specific insulin resistance in adipose tissue may have beneficial effects on whole-body insulin action.…”

Section: Introductionmentioning

confidence: 99%

RETRACTED ARTICLE:l-glutamine supplementation induces insulin resistance in adipose tissue and improves insulin signalling in liver and muscle of rats with diet-induced obesity

et al. 2007

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Aims/hypothesis Diet-induced obesity (DIO) is associated with insulin resistance in liver and muscle, but not in adipose tissue. Mice with fat-specific disruption of the gene encoding the insulin receptor are protected against DIO and glucose intolerance. In cell culture, glutamine induces insulin resistance in adipocytes, but has no effect in muscle cells. We investigated whether supplementation of a highfat diet with glutamine induces insulin resistance in adipose tissue in the rat, improving insulin sensitivity in the whole animal.Materials and methods Male Wistar rats received standard rodent chow or a high-fat diet (HF) or an HF supplemented with alanine or glutamine (HFGln) for 2 months. Light microscopy and morphometry, oxygen consumption, hyperinsulinaemic-euglycaemic clamp and immunoprecipitation/ immunoblotting were performed. Results HFGln rats showed reductions in adipose mass and adipocyte size, a decrease in the activity of the insulininduced IRS-phosphatidylinositol 3-kinase (PI3-K)-protein kinase B-forkhead transcription factor box 01 pathway in adipose tissue, and an increase in adiponectin levels. These results were associated with increases in insulin-stimulated glucose uptake in skeletal muscle and insulin-induced suppression of hepatic glucose output, and were accompanied by an increase in the activity of the insulin-induced IRS-PI3-K-Akt pathway in these tissues. In parallel, there were decreases in TNFα and IL-6 levels and reductions in c-jun N-terminal kinase (JNK), IκB kinase subunit β (IKKβ) and mammalian target of rapamycin (mTOR) activity in the liver, muscle and adipose tissue. There was also an increase in oxygen consumption and a decrease in the respiratory exchange rate in HFGln rats. Conclusions/interpretation Glutamine supplementation induces insulin resistance in adipose tissue, and this is accompanied by an increase in the activity of the hexosamine pathway. It also reduces adipose mass, consequently attenuating insulin resistance and activation of JNK and IKKβ, while improving insulin signalling in liver and muscle.

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Section: Introductionmentioning

confidence: 99%

RETRACTED ARTICLE:l-glutamine supplementation induces insulin resistance in adipose tissue and improves insulin signalling in liver and muscle of rats with diet-induced obesity

et al. 2007

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“…This effect of hyperinsulinaemia dissociating the insulin action in adipose tissue and muscle was also observed in other studies [10,37] in animals with increased adiposity. Our data on insulin signalling is in accordance with previous data [38][39][40][41] showing that hyperinsulinaemia, imposed on normal rats, increases glucose uptake, lipogenesis and fat accumulation in white adipose tissue, whilst producing reduced glucose utilisation.…”

Section: Discussionsupporting

confidence: 84%

“…Dephosphorylation of IR and IRS-1 by protein tyrosine phosphatase 1B (PTP1B) and serine phosphorylation of IRS proteins are believed to be major mechanisms of suppression of IR and IRS protein activities that contribute to insulin resistance [8][9][10]. Both regulation of IR dephosphorylation and serine phosphorylation of IRS proteins have been focused in the search for the molecular mechanism of insulin resistance.…”

Section: Introductionmentioning

confidence: 99%

Regulation of insulin signalling by hyperinsulinaemia: role of IRS-1/2 serine phosphorylation and the mTOR/p70 S6K pathway

et al. 2005

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Aim/hypothesis: Several epidemiological studies have suggested an association between chronic hyperinsulinaemia and insulin resistance. However, the causality of this relationship remains uncertain. Methods: We performed chronic hyperinsulinaemic-euglycaemic clamps and delineated, by western blotting, an IR/IRSs/phosphatidylinositol 3-kinase(PI[3]K)/Akt pathway in insulin-responsive tissues of hyperinsulinaemic rats. IRS-1/2 serine phosphorylation, IR/protein tyrosine phosphatase 1B (PTP1B) association, and mammalian target of rapamycin (mTOR)/ p70 ribosomal S6 kinase (p70 S6K) activity were also evaluated in the liver, skeletal muscle and white adipose tissue of hyperinsulinaemic animals. Results: We found that chronic hyperinsulinaemic rats have insulin resistance and reduced levels of glycogen content in liver and muscle. In addition, we demonstrated an impairment of the insulin-induced IR/IRSs/PI(3)K/Akt pathway in liver and muscle of chronic hyperinsulinaemic rats that parallels increases in IRS1/2 serine phosphorylation, IR/PTP1B association and mTOR activity. Despite a higher association of IR/PTP1B, there was an increase in white adipose tissue of chronic hyperinsulinaemic rats in IRS-1/2 protein levels, tyrosine phosphorylation and IRSs/PI(3)K association, which led to an increase in basal Akt serine phosphorylation. No increases in IRS-1/2 serine phosphorylation and mTOR activity were observed in white adipose tissue. Rapamycin reversed the insulin resistance and the changes induced by hyperinsulinaemia in the three tissues studied. Conclusions/interpretation: Our data provide evidence that chronic hyperinsulinaemia itself, imposed on normal rats, appears to have a dual effect, stimulating insulin signalling in white adipose tissue, whilst decreasing it in liver and muscle. The underlying mechanism of these differential effects may be related to the ability of hyperinsulinaemia to increase mTOR/p70 S6K pathway activity and IRS-1/2 serine phosphorylation in a tissuespecific fashion. In addition, we demonstrated that inhibition of the mTOR pathway with rapamycin can prevent insulin resistance caused by chronic hyperinsulinaemia in liver and muscle. These findings support the hypothesis that defective and tissue-selective insulin action contributes to the insulin resistance observed in hyperinsulinaemic states.

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“…Protein tyrosine phosphatases (PTPs) are extremely sensitive to inhibition by reactive oxygen species via reversible oxidation [45]. Although oxidative stress may facilitate a tyrosine-phosphorylation-dependent cellular signalling response of insulin by transiently inactivating the PTPs that would normally suppress the insulin signal, excessive accumulation of reactive oxygen species under insulin resistance and diabetes has been reported to upregulate the redox-sensitive protein PTP1B [46]. On the other hand, the sucrose-induced increase in PPARγ, the adipocyte-predominant transcription factor found in low abundance in the heart [47], may serve as an insulin sensitiser to regulate glucose and lipid homeostasis [17].…”

Section: Discussionmentioning

confidence: 99%

Metallothionein alleviates cardiac contractile dysfunction induced by insulin resistance: role of Akt phosphorylation, PTB1B, PPARγ and c-Jun

et al. 2005

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Aims/hypothesis: Insulin resistance is concomitant with metabolic syndrome, oxidative stress and cardiac contractile dysfunction. However, the causal relationship between oxidative stress and cardiac dysfunction is unknown. This study was designed to determine the impact of overexpression of the cardiac antioxidant metallothionein on cardiac dysfunction induced by insulin resistance in mice. Methods: Whole-body insulin resistance was generated in wild-type FVB and metallothionein transgenic mice by feeding them with sucrose for 12 weeks. Contractile and intracellular Ca 2+ properties were evaluated in ventricular myocytes using an IonOptix system. The contractile indices analysed included: peak shortening (PS), time to 90% PS (TPS 90 ), time to 90% relengthening (TR 90 ), halfwidth duration, maximal velocity of shortening (+dL/dt) and relengthening (−dL/dt), fura-fluorescence intensity change (ΔFFI) and decay rate (τ). Results: The sucrose-fed mice displayed glucose intolerance, enhanced oxidative stress, hyperinsulinaemia, hypertriglyceridaemia and normal body weight. Compared with myocytes in starch-fed mice, those from sucrose-fed mice exhibited depressed PS, +dL/dt, −dL/ dt, prolonged TR 90 and decay rate, and reduced ΔFFI associated with normal TPS 90 and half-width duration. Western blot analysis revealed enhanced basal, but blunted insulin (15 mU/g)-stimulated Akt phosphorylation. It also showed elevated expression of insulin receptor β, insulin receptor tyrosine phosphorylation, peroxisome proliferatoractivated receptor γ, protein tyrosine phosphatase 1B and phosphorylation of the transcription factor c-Jun, associated with a reduced fold increase of insulin-stimulated insulin receptor tyrosine phosphorylation in sucrose-fed mice. All western blot findings may be attenuated or ablated by metallothionein. Conclusions/interpretation: These data indicate that oxidative stress may play an important role in cardiac contractile dysfunction associated with glucose intolerance and possibly related to alteration in insulin signalling at the receptor and post-receptor levels.

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Modulation of IR/PTP1B interaction and downstream signaling in insulin sensitive tissues of MSG-rats

Cited by 57 publications

References 21 publications

RETRACTED ARTICLE:l-glutamine supplementation induces insulin resistance in adipose tissue and improves insulin signalling in liver and muscle of rats with diet-induced obesity

RETRACTED ARTICLE:l-glutamine supplementation induces insulin resistance in adipose tissue and improves insulin signalling in liver and muscle of rats with diet-induced obesity

Regulation of insulin signalling by hyperinsulinaemia: role of IRS-1/2 serine phosphorylation and the mTOR/p70 S6K pathway

Metallothionein alleviates cardiac contractile dysfunction induced by insulin resistance: role of Akt phosphorylation, PTB1B, PPARγ and c-Jun

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