Activation of MAP kinase by insulin and vanadate in adipocytes from young and old rats

Molero, Juan Carlos; Pérez, Coralia; Martı́nez, Carmen; Villar, Margarita; Andrés, Antonio; Fermín, Yasmín; Carrascosa, J.M.

doi:10.1016/s0303-7207(01)00737-7

Cited by 25 publications

(21 citation statements)

References 52 publications

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“…The same finding is also reported from rat adipocytes stimulated with insulin and inhibited with wortmannin [103][104][105]. One of the reports, [103], also show that the Shc pathway is not involved in the activation of ERK in response to insulin in rat adipocytes.…”

Section: Insulin Control Of Erk Signalingsupporting

confidence: 79%

Insulin signaling dynamics in human adipocytes : Mathematical modeling reveals mechanisms of insulin resistance in type 2 diabetes

Nyman¹

2014

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Type 2 diabetes is characterized by raised blood glucose levels caused by an insufficient insulin control of glucose homeostasis. This lack of control is expressed both through insufficient release of insulin by the pancreatic beta-cells, and through insulin resistance in the insulin-responding tissues. We find insulin resistance of the adipose tissue particularly interesting since it appears to influence other insulin-responding tissues, such as muscle and liver, to also become insulin resistant.The insulin signaling network is highly complex with cross-interacting intermediaries, positive and negative feedbacks, etc. To facilitate the mechanistic understanding of this network, we obtain dynamic, information-rich data and use model-based analysis as a tool to formally test different hypotheses that arise from the experimental observations. With dynamic mathematical models, we are able to combine knowledge and experimental data into mechanistic hypotheses, and draw conclusions such as rejection of hypotheses and prediction of outcomes of new experiments.We aim for an increased understanding of adipocyte insulin signaling and the underlying mechanisms of the insulin resistance that we observe in adipocytes from subjects diagnosed with type 2 diabetes. We also aim for a complete picture of the insulin signaling network in primary human adipocytes from normal and diabetic subjects with a link to relevant clinical parameters: plasma glucose and insulin. Such a complete picture of insulin signaling has not been presented before. Not for adipocytes and not for other types of cells.In this thesis, I present the development of the first comprehensive insulin signaling model that can simulate both normal and diabetic data from adipocytes -and that is linked to a whole-body glucose-insulin model. In the linking process we conclude that at least two glucose uptake parameters differ between the in vivo and in vitro conditions (Paper I). We also perform a model analysis of the early insulin signaling dynamics in rat adipocytes and conclude that internalization is important for an apparent reversed order of phosphorylation seen in these cells (Paper II). In the development of the first version of the comprehensive insulin signaling model, we introduce a key parameter for the diabetic state -an attenuated feedback (Paper III). We finally continue to build on the comprehensive model and include signaling to nuclear transcription via ERK and report substantial crosstalk in the insulin signaling network (Paper IV). Populärvetenskaplig sammanfattningTyp 2-diabetes är en vanligt förekommande sjukdom där kroppens vävnader förlorar sin känslighet mot hormonet insulin. Insulinets uppgift är att hålla en jämn blodsockernivå dygnet runt. Insulin utsöndras i samband med måltider och påverkar muskel-och fettvävnader att ta upp socker och levern att sluta producera socker. Det är viktigt att hålla en jämn blodsockernivå eftersom låga nivåer kan vara direkt dödligt och höga nivåer är skadligt för blodkärlen, vilket i sin tur kan led...

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Section: Insulin Control Of Erk Signalingsupporting

confidence: 79%

Insulin signaling dynamics in human adipocytes : Mathematical modeling reveals mechanisms of insulin resistance in type 2 diabetes

Nyman¹

2014

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“…Studies reveal that in cardiomyocytes from obese Zucker rats, neither insulin nor vanadate could induce glucose uptake or Akt activation to the same extent as in lean control animals, but in combination they elicited a stronger response (92,94). Moreover, chronic exposure to a low concentration of vanadate stimulated glucose uptake, an action mediated via activation of both PI3K and p38 MAPK signaling pathways (93,95). Thus, the ability of vanadium compounds to stimulate glucose transport and glucose oxidation in the myocardium could contribute to the cardioprotective effects observed in various diabetic models following vanadium therapy.…”

Section: Effect Of Vanadium Compounds On the Diabetic Heartmentioning

confidence: 99%

Cardioprotection by Vanadium Compounds Targeting Akt-Mediated Signaling

Bhuiyan

Fukunaga

2009

J Pharmacol Sci

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Abstract. Treatment with inorganic and organic compounds of vanadium has been shown to exert a wide range of cardioprotective effects in myocardial ischemia/reperfusion-induced injury, myocardial hypertrophy, hypertension, and vascular diseases. Furthermore, administration of vanadium compounds improves cardiac performance and smooth muscle cell contractility and modulates blood pressure in various models of hypertension. Like other vanadium compounds, we documented bis(1-oxy-2-pyridinethiolato) oxovanadium (IV) [VO(OPT)] as a potent cardioprotective agent to elicit cardiac functional recovery in myocardial infarction and pressure overload-induced hypertrophy. Vanadium compounds activate Akt signaling through inhibition of protein tyrosine phosphatases, thereby eliciting cardioprotection in myocardial ischemia / reperfusion-induced injury and myocardial hypertrophy. Vanadium compounds also promote cardiac functional recovery by stimulation of glucose transport in diabetic heart. We here discuss the current understanding of mechanisms underlying vanadium compound-induced cardioprotection and propose a novel therapeutic strategy targeting for Akt signaling to rescue cardiomyocytes from heart failure.

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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%

“…32 P]ATP, and phospho-MBP was resolved on 12% SDS-PAGE, detected by autoradiography, and quantitated by scanning densitometry as previously described (35). Alternatively, bands were cut off of the gel and phospho-MBP was quantitated by scintillation counting.…”

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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Activation of MAP kinase by insulin and vanadate in adipocytes from young and old rats

Cited by 25 publications

References 52 publications

Insulin signaling dynamics in human adipocytes : Mathematical modeling reveals mechanisms of insulin resistance in type 2 diabetes

Insulin signaling dynamics in human adipocytes : Mathematical modeling reveals mechanisms of insulin resistance in type 2 diabetes

Cardioprotection by Vanadium Compounds Targeting Akt-Mediated Signaling

Leptin Impairs Insulin Signaling in Rat Adipocytes

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