Insulin sensitivity and glucose metabolism -
Two hours later, muscle, liver and fat tissues were removed and single-cell suspensions from each of those tissues were tested by fluorescence activated cell sorting FACS for the presence of 2-NBDG. We produced a model for type 2 diabetes by feeding a high-fat diet TD. Thirteen weeks later, the mice were injected i.
with µg of 2-NBDG. Two hours after injection, muscle and liver tissues were removed and analyzed for glucose uptake as described above. This value was obtained by all mice after 13 weeks on the diet. Prior to euthanasia of mice, fasting serum insulin levels were determined by ELISA according to the manufacture's instructions.
To test the hypothesis that Ras inhibition results in increased uptake of glucose in muscle cells, we induced C2C12 cell differentiation into myotubes see Methods and transfected the differentiated muscle cells with DN-GFP-labeled Ras or a GFP-labeled control plasmid.
We then induced insulin resistance in all cells by addition of palmitate see Methods and assayed their ability to absorb fluorescent glucose. In line with previous reports [35] , palmitate reduced glucose uptake compared to BSA-treated control cells not shown.
These results suggest that active Ras inhibition may upregulate glucose absorption. Insulin-resistant C2C12 myotubes were transfected with DN-Ras-GFP or GFP plasmid pGFP and fluorescent glucose uptake was measured by flow cytometry.
Statistical analysis of the results is presented as means ± S. IκB, NF-κB and tubulin expression in the DN-Ras transfected or GFP-transfected myotubes were assayed by western blotting, as described in Material and Methods. Densitometry of IκB and NF-κB expression.
The nuclear transcription factor NF-κB and its inhibitor IκB have been shown to participate in the induction of insulin resistance by palmitate. To study the effect of Ras inhibition on NF-κB and IκB in the insulin-resistant C2C12 cells, we assayed IκB and NF-κB in these cells following DN-Ras transfection.
To verify the effect of Ras inhibition on glucose uptake, we used F-FTS, a small molecule that interferes with anchorage of Ras to the membrane and hence inhibits Ras function [29] , [31]. First, we examined whether F-FTS mimics the observed effect of DN-Ras on glucose uptake in C2C12 myotubes.
In line with this effect of F-FTS on glucose uptake was the finding that expression of the mRNA glucose transporter 4 glut-4 was induced by F-FTS. Insulin-resistant C2C12 myotubes were incubated with or without F-FTS 50 µM , and were then assayed for their ability to absorb fluorescent glucose.
Densitometry of Glut4 is shown. I K B, NF-κB, p-I K B and tubulin were assayed by western blotting as described in Methods. Densitometry of IκB, p-I K B and NF-κB expression. These findings are consistent with the results obtained by treatment with DN-Ras. To determine whether the enhanced glucose uptake resulting from treatment with DN-Ras in vitro Figs.
with DN-GFP-Ras or with pGFP, as described in Methods. Representative histograms of glucose uptake are presented for each tissue. Testing of the above tissues for Ras-GTP expression revealed a significant decrease, concomitantly with the effects on glucose uptake Fig.
No significant differences in glucose uptake were observed in the fat tissues data not shown. IκB, NF-κB and tubulin in the tissues were assayed by western blotting, as described in Methods.
No differences were found in the liver tissue data not shown. Having shown that Ras inhibition by F-FTS mimics the effect of DN-Ras on glucose uptake both in vitro and in vivo , we next examined the effect of long-term treatment with F-FTS or FTS on the development of hyperglycemia in an experimental model of type 2 diabetes.
To examine how the effectiveness of the drugs was influenced by the route of administration, we treated the mice either intraperitoneally i. or per os p. Similar results were observed when mice were treated p. Kaplan-Meier plots of mean incidence of diabetes in each group.
Kaplan-Meier curves record the mean incidence of diabetes in each group. All treated animals were monitored for weight gain while being fed a high-fat diet. Kaplan-Meier curves record the mean percentage of weight gain in each group. As expected, the high-fat diet caused a significant increase in body weight in all treated groups [36].
No significant differences in weight gain were observed between the i. F-FTS-treated and PBS-treated groups or between the p. o FTS-treated, F-FTS-treated and CMC-treated groups Fig.
We also assayed circulating insulin in the different groups of mice. After i. treatment, the levels of circulating insulin were significantly decreased in the F-FTS-treated group 4. In the orally treated mice, insulin concentrations in the F-FTS-treated and the FTS-treated groups were also significantly reduced 7.
Activated Ras plays an important role in modulating a number of signaling molecules that trigger cell proliferation, differentiation, and survival [37] , [38]. These observations are in line with several studies showing that Ras inhibition attenuates inflammatory responses in experimental models [25] , [31] , [39] , [40].
Resistance to insulin, resulting in decreased glucose uptake, is a major factor contributing to the development of type 2 diabetes [41]. The mechanisms responsible for inducing resistance to insulin are not completely understood, but accumulating data point to a robust association between insulin resistance and inflammation.
Obesity promotes insulin resistance by resulting in a state of chronic inflammation that involves production of proinflammatory cytokines TNF-α, IL-6 , an increase in the number of macrophages, and activation of a complex cascade of signaling events in muscle, fat and liver tissues [6] , [35] , [42].
Consistent with these findings, we showed here for the first time that inhibition of Ras by DN-Ras or F-FTS, promoted anti-inflammatory response in a muscle cell line and in mouse tissues. This study is the first to show a clear association between Ras signaling and insulin resistance in muscle, fat and liver.
We found that inhibition of Ras activation by transfection with DN-Ras or by treatment with the small-molecule Ras inhibitor F-FTS induced glucose uptake in vitro , indicating higher insulin sensitivity.
In addition, we demonstrated that inhibition of Ras in vivo by hydrodynamic injection of DN-Ras or by daily treatment with F-FTS in an experimental murine model of HF-induced diabetes resulted in similar findings of increased uptake of fluorescently labeled glucose by muscle, fat and liver tissues.
To characterize the signaling pathway by which Ras inhibition promotes insulin sensitivity, we studied the expression of key regulators known to participate in insulin-signaling pathways. IκB kinase IKK phosphorylates certain serine residues on insulin receptor kinase 1 IRS-1 , leading to impairment of insulin signal transduction.
In addition, the IKK signaling pathway is upregulated and activated, both in insulin-resistant humans and in rodent skeletal muscles [43]. Increased expression of IKK results in inhibition of IκB and activation of NF-κB ; the latter subsequently transcriptionally activates a set of inflammatory pathway genes that induce resistance to insulin see scheme, Fig.
Free fatty acids FFAs lead to activation of IKK, the inhibitor of IκB kinase. IKK affects insulin sensitivity and glucose uptake via two distinct pathways.
First, IKK phosphorylates insulin receptor substrate 1 IRS-1 , resulting in inactivation of insulin signaling through attenuated transcription of glucose transporter 4 Glut4. Ras inhibition by F-FTS demonstrates enhanced Glut4 transcription, hence also heightened glucose uptake.
Second, IKK phosphorylates the inhibitor of κB IκB , causing it to become detached from nuclear factor κB NF-κB. NF-κB enters the nucleus and induces transcription of proinflammatory cytokines such as IL-6 and TNF-α.
These cytokines leads to deterioration of insulin resistance. Ras inhibition by DN-Ras or by F-FTS augments IκB expression, thereby attenuating the proinflammatory response and enhancing insulin sensitivity and glucose uptake. We found that Ras inhibition led to an increase in IκB, which inhibited the expression of NF-κB both in vitro and in vivo Figs.
The improvement in glucose uptake in liver tissue of the F-FTS treated animals was not correlated with increased expression of IκB Fig 4. This finding could result from the long period 13 weeks of treatment that may influence the duration of the increased IκB expression.
Overall, the observation that insulin resistance was attenuated by Ras inhibition in association with regulation of IκB and NF-κB provides a possible link between Ras, inflammation, and negative regulation of insulin signaling.
The most downstream factor in the insulin cascade is Glut4, an essential transporter responsible for translocation of insulin-regulated glucose into the cell [45]. We therefore examined the effect of Ras inhibition on Glut4 mRNA levels in insulin-resistant C2C12 myotubes treated with F-FTS.
We found an increase in Glut4 mRNA levels after F-FTS treatment. These results suggested that the higher sensitivity to insulin was attributable to Ras inhibition, which may be related to the increase in expression of Glut4 transporter in the plasma membrane and the subsequent potentiated influx of glucose into the cell see scheme, Figure 6.
Taken together, our results suggest dual affects of Ras on insulin sensitivity and glucose uptake via two distinct pathways Figure 6.
Previous studies have shown that both FTS and the small synthetic molecule F-FTS act primarily by inhibiting active Ras proteins and are mimicked by dominant negative Ras [30] , [46].
Therefore, mice fed a high-fat diet and concomitantly treated with F-FTS may serve as an appropriate in vivo model for examining the effect of Ras inhibition on an experimental model of type 2 diabetes. Our results showed that treatment with either FTS or F-FTS significantly attenuated the incidence of hyperglycemia in this model.
The potential contribution of Ras-mediated insulin sensitization in this in vivo model is supported by the finding that circulating insulin levels were decreased in the FTS-treated mice Fig. The observed decrease of insulin level most likely resulted from the increased uptake of glucose into the tissues but could also be caused by a direct effect on the pancreas.
Further studies should be performed to clarify the cause of the decrease in serum insulin levels. Taken together, the results of this study showed that inhibition of Ras signaling enhances both insulin sensitivity and glucose uptake in vitro and in vivo.
These observations were corroborated by the beneficial effects of Ras inhibition that resulted in attenuation of hyperglycemia in a conventional type 2 diabetes model. It should be noted, however, that Ras inhibition may modify inflammatory responses in other tissues as well.
These findings pave the way for a novel approach to the potential treatment of insulin resistance and type 2 diabetes.
Conceived and designed the experiments: AM EA JG YK. Performed the experiments: AM EA. Analyzed the data: AM EA JG YK. Wrote the paper: AM EA JG YK. Browse Subject Areas? Click through the PLOS taxonomy to find articles in your field. Article Authors Metrics Comments Media Coverage Reader Comments Figures.
Abstract Background Reduced glucose uptake due to insulin resistance is a pivotal mechanism in the pathogenesis of type 2 diabetes. Methods and Findings The effect of Ras inhibition on glucose uptake was examined both in vitro and in vivo. Conclusions Inhibition of Ras apparently induces a state of heightened insulin sensitization both in vitro and in vivo.
Introduction Insulin resistance is defined as impaired sensitivity to insulin in its main target organs muscle, liver and adipose tissues , and is considered a hallmark of type 2 diabetes [1]. Materials and Methods Induction of insulin resistance in cell culture Mouse C2C12 myoblasts generously provided by Prof.
Transfection with dominant-negative Ras To block Ras we transfected differentiated C2C12 cells with 2 7g of green fluorescent protein plasmid pGFP or dominant-negative DN GFP-Ras 17N , using lipofectamine reagent according to manufacture's instructions Invitrogen, Carlsbad, CA, USA.
Western blotting To examine the impact of Ras inhibition on IκB and NF-κB, we performed Western immunoblotting with specific antibodies.
Glut4 expression determined by reverse transcription—PCR RNA was extracted from 10 6 C2C12 muscle cells using an RNeasy Mini Kit Qiagen, Hilden, Germany according to the manufacturer's instructions.
In vivo studies The study was approved by the Institutional Ethics Committee at the Tel Aviv Sourasky Medical Center, Tel Aviv, Israel Approval ID is L Download: PPT. Figure 1. Figure 2. Ras inhibition by hydrodynamic injection of DN-Ras induces glucose uptake in vivo To determine whether the enhanced glucose uptake resulting from treatment with DN-Ras in vitro Figs.
Figure 3. Ras inhibition in vivo increases muscle, fat and liver glucose uptake. Figure 4. Ras inhibition by F-FTS attenuates type 2 diabetes in vivo and reduces circulating insulin levels Having shown that Ras inhibition by F-FTS mimics the effect of DN-Ras on glucose uptake both in vitro and in vivo , we next examined the effect of long-term treatment with F-FTS or FTS on the development of hyperglycemia in an experimental model of type 2 diabetes.
Figure 5. Ras inhibition in HF-induced diabetic mice reduces diabetes incidence and increases the concentration of circulating insulin. Discussion Activated Ras plays an important role in modulating a number of signaling molecules that trigger cell proliferation, differentiation, and survival [37] , [38].
Figure 6. Proposed mechanism explaining the effect of Ras on insulin sensitivity. Acknowledgments We thank S. Smith for editorial assistance. Author Contributions Conceived and designed the experiments: AM EA JG YK.
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Ich meine, dass es die Unwahrheit ist.