Pharmacological inhibition of S6K1 increases glucose metabolism and Akt signalling in vitro and in diet-induced obese mice

Shum, Michaël; Bellmann, Kerstin; St-Pierre, Philippe; Marette, André

doi:10.1007/s00125-015-3839-6

Cited by 48 publications

(52 citation statements)

References 50 publications

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“…The phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B (PI3K/Akt) signaling pathway was suppressed in diabetes[53, 54]. Our results showed that TLR4 interfering suppressed the PI3K/Akt pathway, mitigating the abnormal mesangial cell proliferation.…”

Section: Discussionmentioning

confidence: 65%

High Glucose Induces Mouse Mesangial Cell Overproliferation via Inhibition of Hydrogen Sulfide Synthesis in a TLR-4-Dependent Manner

Ding¹,

Chen²,

Li³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Overproliferation of mesangial cells was believed to play an important role in the progress of diabetic nephropathy, one of the primary complications of diabetes. Hydrogen sulfide (H₂S), a well-known and pungent gas with the distinctive smell of rotten eggs, was discovered to play a protective role in diabetic nephropathy. Methods: MTT assay was used to examine the viability of mesangial cells. Small interfering RNA was used to knock down the expression of TLR4 while specific inhibitor LY294002 to suppress the function of PI3K. H₂S generation rate was determined by a H₂S micro-respiration sensor. Results: Glucose of 25mM induced significant mesangial cells proliferation, which was accomplished by significantly inhibited endogenous H₂S synthesis. And exogenous H₂S treatment by NaHS markedly mitigated the overproliferation of mouse mesangial cells. Furthermore, it was found that H₂S deficiency could result in TLR4 activation. And H₂S supplementation remarkably inhibited TLR4 expression and curbed the mesangial cell overproliferation. Besides, PI3K/Akt pathway inhibition also significantly ameliorated the cell overproliferation. Conclusion: High glucose (HG) induces mouse mesangial cell overproliferation via inhibition of hydrogen sulfide synthesis in a TLR-4-dependent manner. And PI3K/Akt pathway might also play a vital part in the HG-induced mesangial cell overproliferation.

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Section: Discussionmentioning

confidence: 65%

High Glucose Induces Mouse Mesangial Cell Overproliferation via Inhibition of Hydrogen Sulfide Synthesis in a TLR-4-Dependent Manner

Ding¹,

Chen²,

Li³

et al. 2017

Cell Physiol Biochem

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“…S6K1 has been recently pursued as a molecular target for sensitizing the insulin receptor and for controlling hyperglycemia . Shum et al .…”

Section: Discussionmentioning

confidence: 99%

“…S6K1 has been recently pursued as a molecular target for sensitizing the insulin receptor and for controlling hyperglycemia. [29] Shum et al [29] reported that PF-4708671, a specific inhibitor of S6K1, sensitizes the insulin receptor and enhances glucose uptake. We recently identified S6K1 as a molecular target of A77 1726, the active metabolite of anti-rheumatoid arthritis (RA) drug leflunomide.…”

Section: Discussionmentioning

confidence: 99%

“…[6] We and others recently reported that S6K1 inhibitors such as PF-4708671 and leflunomide can control hyperglycemia in type 2 diabetic mouse models. [29,33] The antihyperglycemic and anti-obesity effects of leflunomide have been observed in leflunomide-treated RA patients. [46,47] Leflunomide could be a leading candidate for treating type 2 diabetes since the side effects of this clinically approved drug have been well characterized.…”

Section: Discussionmentioning

confidence: 99%

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Gingerenone A Sensitizes the Insulin Receptor and Increases Glucose Uptake by Inhibiting the Activity of p70 S6 Kinase

Chen¹,

Sun²,

Prinz

et al. 2018

Molecular Nutrition Food Res

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Scope: The bioactive constituents in ginger extract responsible for their anti-hyperglycemic effect and the underlying mechanisms are incompletely understood. Gingerenone A (Gin A) has been identified as an inhibitor of p70 S6 (S6K1), a kinase that plays a critical role in the pathogenesis of insulin resistance. Our study aims to evaluate if Gin A can sensitizes the insulin receptor by inhibiting S6K1 activity. Methods and results: Western blot analysis revealed that Gin A induced phosphatidylinositide-3 kinase (PI3K) feedback activation in murine 3T3-L1 adipocytes and rat L6 myotubes, as evidenced by increased AKTS473 and S6K1T389 but decreased S6S235/236 and insulin receptor substrate 1 (IRS-1)S1101 phosphorylation. Western blot and immunoprecipitation analysis revealed that Gin A increased insulin receptor tyrosine phosphorylation in L6 myotubes and IRS-1 binding to the PI3K in 3T3-L1 adipocytes. Confocal microscopy revealed that Gin A enhanced insulin-induced translocation of glucose transporter 4 (GLUT4) into the cell membrane in L6 cells. 2-NBDG(2-N-(Nitrobenz-2-oxa-1,3-diazol-4-yl)amino)−2-deoxyglucose) fluorescent assay revealed that Gin A enhanced insulin-stimulated glucose uptake in 3T3-L1 adipocytes and L6 myotubes. Conclusions: Gin A overcomes insulin resistance and increases glucose uptake by inhibiting S6K1 activity. Gin A or other plant-derived S6K1 inhibitors could be developed as novel anti-diabetic agents.

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“…Thus, PF-4708671 had been used in studies determining the role of S6K1 and mTORC1 in physiological and pathological conditions [25][26][27][28]. The inhibitory effect of PF-4708671 on S6K was confirmed by measuring the phosphorylation of S6, which is a downstream target of S6K, in previous studies [22,[25][26][27][28]. Therefore, we similarly examined effects of PF-4708671 on pS6 levels in retinas.…”

Section: Discussionmentioning

confidence: 92%

Protective effects of PF‐4708671 against N‐methyl‐d‐aspartic acid‐induced retinal damage in rats

Hayashi

Aoki

Ushikubo

et al. 2016

Fundamemntal Clinical Pharma

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We previously demonstrated that rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), protects against N-methyl-d-aspartic acid (NMDA)-induced retinal damage in rats. Rapamycin inhibits mTOR activity, thereby preventing the phosphorylation of ribosomal protein S6, which is a downstream target of S6 kinase. Therefore, we aimed to determine whether PF-4708671, an inhibitor of S6 kinase, protects against NMDA-induced retinal injury. Intravitreal injection of NMDA (200 nmol/eye) caused cell loss in the ganglion cell layer and neuroinflammatory responses, such as an increase in the number of CD45-positive leukocytes and Iba1-positive microglia. Surprisingly, simultaneous injection of PF-4708671 (50 nmol/eye) with NMDA significantly attenuated these responses without affecting phosphorylated S6 levels. These results suggest that PF-4708671 and rapamycin likely protect against NMDA-induced retinal damage via distinct pathways. The neuroprotective effect of PF-4708671 is unlikely to be associated with inhibition of the S6 kinase, even though PF-4708671 is reported to be a S6 kinase inhibitor.

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Pharmacological inhibition of S6K1 increases glucose metabolism and Akt signalling in vitro and in diet-induced obese mice

Cited by 48 publications

References 50 publications

High Glucose Induces Mouse Mesangial Cell Overproliferation via Inhibition of Hydrogen Sulfide Synthesis in a TLR-4-Dependent Manner

High Glucose Induces Mouse Mesangial Cell Overproliferation via Inhibition of Hydrogen Sulfide Synthesis in a TLR-4-Dependent Manner

Gingerenone A Sensitizes the Insulin Receptor and Increases Glucose Uptake by Inhibiting the Activity of p70 S6 Kinase

Protective effects of PF‐4708671 against N‐methyl‐d‐aspartic acid‐induced retinal damage in rats

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