Vanadate fully stimulates insulin receptor substrate‐1 associated phosphatidyl inositol 3‐kinase activity in adipocytes from young and old rats

Molero, Juan Carlos; Martı́nez, Carmen; Andrés, Antonio; Satrústegui, Jorgina; Carrascosa, Jóse M.

doi:10.1016/s0014-5793(98)00258-0

Cited by 40 publications

(28 citation statements)

References 49 publications

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“…However, there is a marked impairment of both IR autophosphorylation and its intrinsic tyrosine kinase activity during aging (Ruiz et al 1992). Moreover, in isolated adipocytes from old rats we have also shown that insulin stimulation of IRS-1-associated PI3K, glucose uptake and glucose transporter 4 (GLUT4) translocation to the plasma membrane is reduced (Molero et al 1998).…”

Section: Introductionmentioning

confidence: 77%

“…We have previously shown that insulin-resistant adipocytes from old rats are characterized by decreased IR autophosphorylation and by impaired insulin stimulation of IRS-1-associated PI3K activity, GLUT4 translocation to the plasma membrane, glucose uptake and MAPK activity (Carrascosa et al 1989, Molero et al 1998. These data can partially be explained with the results presented here because insulin signaling is dependent on IR and IRS activation, and we show that aging down-regulates the expression of IR-B (the isoform considered to transmit the insulin signal more efficiently).…”

Section: Effect Of Aging On Ir and Irs Protein Expression In Isolatedmentioning

confidence: 99%

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Differential gene expression of insulin receptor isoforms A and B and insulin receptor substrates 1, 2 and 3 in rat tissues: modulation by aging and differentiation in rat adipose tissue

Serrano

Villar²,

Martı́nez

et al. 2005

Journal of Molecular Endocrinology

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The insulin receptor (IR) occurs as two alternatively spliced isoforms, IR-A (exon 11−) and IR-B (exon 11+), which exhibit functional differences and are expressed in a tissue-specific manner. The IR substrate (IRS) proteins 1, 2 and 3 also differ in function and tissue distribution. Here we show the differential gene expression of IRs and IRSs in several rat target tissues of insulin action. IR-B is significantly higher than IR-A in epididymal white adipose tissue and adipogenesis induces a shift in the alternatively spliced species of IR from the A to the B isoform. Moreover, since aging in the rat is associated with the development of insulin resistance we looked for alterations of expression of these proteins in adipocytes from old rats. Our results reveal that there is a specific decrease in the expression of the IR-B isoform, as well as both mRNA and protein levels of IR, IRS-1 and IRS-3 being significantly decreased, in epididymal adipose tissue from old compared with adult rats. It is concluded that the down-regulation of early components of the insulin transduction pathway in a primary insulin target tissue could be related to the insulin resistance of aging.

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Section: Introductionmentioning

confidence: 77%

Section: Effect Of Aging On Ir and Irs Protein Expression In Isolatedmentioning

confidence: 99%

Differential gene expression of insulin receptor isoforms A and B and insulin receptor substrates 1, 2 and 3 in rat tissues: modulation by aging and differentiation in rat adipose tissue

Serrano

Villar²,

Martı́nez

et al. 2005

Journal of Molecular Endocrinology

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“…Consequently, glucose-uptake is related to the inhibition of FFA-release from isolated rat adipocytes treated with epinephrine. 28,29,48) Vanadium compounds are considered to activate IRS, 49) PI3-K, 50) GLUT-4, 51,52) cyclic nucleotide phosphodiesterases (PDEs), 53) and protein tyrosine phosphatases (PTPs), 54,55) analogous with the action of insulin. While, vanadyl ions inhibit FFA-release from adipocytes treated with epinephrine.…”

Section: Discussionmentioning

confidence: 99%

“…[57][58][59][60] Vanadium at 1 mM has been found to stimulate the IRS-1 associated with PI3-K activity and GLUT-4 translocation without activating the insulin receptor in rats. 49) In these previous reports, it was considered that glucose-uptake into the cell by vanadium compounds was stimulated without activating the insulin receptor. Such poor evidence for the contribution of vanadium compounds to the insulin receptor suggests the concentration-dependent affinity of vanadium compounds for intracellular enzymes and substrates.…”

Section: Discussionmentioning

confidence: 99%

Insulin-Mimetic Vanadyl(IV) Complexes as Evaluated by Both Glucose-Uptake and Inhibition of Free Fatty Acids (FFA)-Release in Isolated Rat Adipocytes

Adachi

Sakurai

2004

CHEMICAL & PHARMACEUTICAL BULLETIN

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We have recently proposed the existence of some potent vanadyl complexes with blood glucose-lowering activity in experimental diabetic animals based on the results of an in vitro FFA (free fatty acids)-release assay in isolated rat adipocytes treated with epinephrine and evidence of an in vivo blood glucose lowering effect in experimental diabetic animals. However, the FFA assay depends indirectly on the glucose-uptake of vanadyl complexes in adipocytes. It is therefore necessary to develop a more reliable in vitro glucose-uptake assay, in place of the glucose uptake method using radioactive compounds such as 14 C-glucose, to identify insulin-mimetic vanadyl complexes. In the present study, we proposed a combined in vitro assay by using the conventional glucose oxidase method for glucose-uptake and FFA assay in isolated rat adipocytes. Insulin, vanadyl sulfate (VOSO 4 ), bis(picolinato)vanadyl (VO(pa) 2 ), and bis(6-methylpicolinato)vanadyl (VO(6mpa) 2 ) complexes exhibited concentration-dependent uptake of (؉)-D-glucose and inhibition of FFA release in the adipocytes treated with epinephrine. Vanadyl complexes were found to accelerate glucose-uptake at lower concentrations than VOSO 4 . In vitro high insulin-mimetic activity of VO(pa) 2 and VO(6mpa) 2 were thus indicated by both glucose-uptake and FFA-release, with the insulin-mimetic activity of VO(6mpa) 2 being higher than that of VO(pa) 2 , as suggested by the partition coefficient (0.330 for VO(pa) 2 and 0.595 for VO(6mpa) 2 ). The proposed assay provides a more reliable method than each single method for the evaluation of in vitro insulin-mimetic activity of compounds.Key words vanadyl compound; glucose-uptake assay; free fatty acids (FFA)-release assay; insulin-mimetic effect; adipocyte 428

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“…Following the treatment, cells were incubated in the absence or presence of 16 nmol/l porcine insulin or 1 mmol/l Na 3 VO 4 (Sigma). After 5 min, the medium was aspirated, cells were washed in PBS, lysed in homogenization buffer, and centrifuged at 8,000g for 30 min as previously described (34,35). Infranatants (cytosolic extracts) were used for determination of mitogen-activated protein kinase (MAPK) activity and glycogen synthase kinase (GSK)3 phosphorylation.…”

Section: Isolation and Fractionation Of Adipocytes For In Vitro Expermentioning

confidence: 99%

Leptin Impairs Insulin Signaling in Rat Adipocytes

et al. 2004

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Leptin modulates glucose homeostasis by acting as an insulin-sensitizing factor in most insulin target tissues. Nevertheless, insulin-dependent glucose uptake in white adipose tissue decreases after in vivo treatment with leptin. Moreover, elevated leptin concentrations inhibit insulin metabolic effects in adipocytes. Here we studied both, direct and centrally mediated effects of leptin on insulin signaling in rat adipocytes. Adipocyte incubation with low leptin concentrations did not modify the insulin stimulation of mitogen-activated protein kinase (MAPK). However, at elevated concentrations, leptin impaired insulin-stimulated MAPK activity, glycogen synthase kinase (GSK)3␤ phosphorylation, and insulin receptor tyrosine phosphorylation without altering vanadate stimulation. An increase of suppressor of cytokine signaling-3 protein was also observed. Central administration of leptin decreased insulin effects on adipocyte MAPK and GSK3␤ phosphorylation. In insulin-resistant aged rats with hyperleptinemia and central leptin resistance, insulin poorly stimulated MAPK and central leptin infusion did not further deteriorate adipocyte insulin responsiveness. Food restriction increased MAPK stimulation by insulin and restored the ability of centrally infused leptin to attenuate adipocyte insulin signaling in aged rats. We conclude that leptin can modulate, in an inhibitory manner, adipocyte insulin signaling by two different ways: as an autocrine signal and, indirectly, through neuroendocrine pathways. These mechanisms may be of relevance in situations of hyperleptinemia, such as aging and/or obesity. Diabetes 53

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Vanadate fully stimulates insulin receptor substrate‐1 associated phosphatidyl inositol 3‐kinase activity in adipocytes from young and old rats

Cited by 40 publications

References 49 publications

Differential gene expression of insulin receptor isoforms A and B and insulin receptor substrates 1, 2 and 3 in rat tissues: modulation by aging and differentiation in rat adipose tissue

Differential gene expression of insulin receptor isoforms A and B and insulin receptor substrates 1, 2 and 3 in rat tissues: modulation by aging and differentiation in rat adipose tissue

Insulin-Mimetic Vanadyl(IV) Complexes as Evaluated by Both Glucose-Uptake and Inhibition of Free Fatty Acids (FFA)-Release in Isolated Rat Adipocytes

Leptin Impairs Insulin Signaling in Rat Adipocytes

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