Insulin Promotes Glucose Consumption via Regulation of miR-99a/mTOR/PKM2 Pathway

Li, Wei; Wang, Jing; Chen, Qiu Dan; Qian, Xu; Li, Qi; Yin, Yuan; Shi, Zhu; Wang, Lin; Lin, Jie; Liu, Lingzhi; Jiang, Bing-Hua

doi:10.1371/journal.pone.0064924

Cited by 35 publications

(27 citation statements)

References 53 publications

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“…Rapamycin, the inhibitor of mTORC1 pathway, is a regulator of the glycolytic flux in mammalian cells (41). The mTORC1 pathway controls glucose metabolism and glycolysis through regulation of glucose transporters and rate-limiting glycolytic enzymes (42, 43). In human skeletal muscle, rapamycin administration augmented glucose uptake in the presence of combined hyperaminoacidemia and prandial-like peripheral hyperinsulinemia (44).…”

Section: Discussionmentioning

confidence: 99%

Mammalian target of rapamycin controls glucose consumption and redox balance in human Sertoli cells

Jesus

Oliveira

Silva

et al. 2016

Fertility and Sterility

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Objective To study the role of mammalian target of rapamycin (mTOR) in the regulation of human Sertoli cell (hSC) metabolism, mitochondrial activity, and oxidative stress. Design Experimental study. Setting University research center and private assisted reproductive technology centers. Patient(s) Six men with anejaculation (psychological, vascular, neurologic) and conserved spermatogenesis. Intervention(s) Testicular biopsies were used from patients under treatment for recovery of male gametes. Primary hSCs cultures were established from each biopsy and divided into a control group and one treated with rapamycin, the inhibitor of mTOR, for 24 hours. Main Outcome Measure(s) Cytotoxicity of hSCs to rapamycin was evaluated by sulforhodamine B assay. The glycolytic profile of hSCs was assessed by proton nuclear magnetic resonance and by studying protein expression of key glycolysis-related transporters and enzymes. Expression of mitochondrial complexes and citrate synthase activity were determined. Protein carbonylation, nitration, lipid peroxidation, and sulfhydryl protein group contents were quantified. The mTOR signaling pathway was studied. Result(s) Rapamycin increased glucose consumption by hSCs, maintaining lactate production. Alanine production by rapamycin-exposed hSCs was affected, resulting in an unbalanced intracellular redox state. Rapamycin-exposed hSCs had decreased expression of mitochondrial complex III and increased lipid peroxidation, whereas other oxidative stress markers were unaltered. Treatment of hSCs with rapamycin down-regulated phospho-mTOR (Ser-2448) levels, illustrating an effective partial inhibition of mTORC1. Protein levels of downstream signaling molecule p-4E-BP1 were not altered, suggesting that during treatment it became rephosphorylated. Conclusion(s) We show that mTOR regulates the nutritional support of spermatogenesis by hSCs and redox balance in these cells.

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Section: Discussionmentioning

confidence: 99%

Mammalian target of rapamycin controls glucose consumption and redox balance in human Sertoli cells

Jesus

Oliveira

Silva

et al. 2016

Fertility and Sterility

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“…The successful transfection was further verified by Western blot detecting targets of miR99a ( Figure 2B): insulin like growth factor 1 receptor (IGF1R) and mechanistic target of rapamycin (mTOR), whose protein levels can be inhibited by miR-99a according to previous reports. 20,21) Consistently, miR-99a mimic suppressed and its inhibitor promoted IGF1R and mTOR protein levels, suggesting that miR-99a level was effectively changed in H9c2 cells, which could be used in further experiments.…”

Section: Mir-99a Attenuates Lps-induced Oxidative Injury In H9c2 Cellsmentioning

confidence: 80%

microRNA-99a Reduces Lipopolysaccharide-Induced Oxidative Injury by Activating Notch Pathway in H9c2 Cells

et al. 2017

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SummarymicroRNA-99a (miR-99a) is recently recognized as a key regulator in various cancers and cardiovascular diseases. In the present study, we sought to investigate the effects of miR-99a in rat cardiomyocyte H9c2 cells against oxidative injury induced by lipopolysaccharide (LPS).MTT assay, reactive oxygen species (ROS) assay, flow cytometry and lactate dehydrogenase (LDH) assay were respectively used to explore viability, ROS levels, apoptosis, and cell death in H9c2 cells. Quantitative PCR (qRT-PCR) was performed to confirm the expression of miR-99a. Western blot was performed to determine the expression of Notch pathway factors.LPS could significantly suppress viability and increase cell death, apoptosis, and ROS level (P < 0.05). However, miR-99a could significantly increase the viability and decrease apoptosis and ROS level of H9c2 cells (P < 0.05). Overexpression of miR-99a could activate a Notch pathway and regulate the expression of B-cell CLL/lymphoma 2 (BCL2) and cleaved caspase 3.Our study found that overexpression of miR-99a could attenuate LPS-induced oxidative injury in H9c2 cells, possibly via a Notch pathway. These findings suggest that miR-99a may be a key factor in cardiomyocyte oxidative injury and could be a new therapeutic strategy for cardiovascular diseases. (Int Heart J 2017; 58: 422-427)

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“…HIF-1a was known to be involved in the insulin signaling pathway and to be regulated via Akt signaling pathway (Fang et al, 2007;Yu et al, 2012). Other studies reported insulin could increase the expression of mTOR and HIF-1a in HepG2 and HL7702 cells (Li et al, 2013). IL-1b up-regulated HIF-1a and DEC1 in human primary gingival cells via the Akt pathway (Bhawal et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Decreased carboxylesterases expression and hydrolytic activity in type 2 diabetic mice through Akt/mTOR/HIF-1α/Stra13 pathway

et al. 2015

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1. This study investigated the alteration of carboxylesterases in type 2 diabetes. We found that the carboxylesterase 1d (Ces1d) and carboxylesterase 1e (Ces1e) expression and the capacity of hydrolytic activity of liver and intestine decreased, whereas the Akt/mTOR/HIF-1α/ Stra13 (DEC1) signaling was activated in T2D mice. Consistently, high insulin could give rise to the same results in the high-glucose DMEM condition, which mimicked T2D, in primary mouse hepatocytes. 2. Perifosine or rapamycin almost abolished the decrease of the Ces1d and Ces1e expression and the hydrolytic activity induced by the insulin in the primary mouse hepatocytes. 3. The responsiveness of human hepatoma (HepG2) cells to high insulin in high-glucose condition was similar to that of primary mouse hepatocytes in terms of the altered expression of carboxylesterases. 4. The knockdown of HIF-1α or DEC1 with shRNA construct abrogated the decrease of the CES1 and CES2 expression induced by the insulin in high glucose condition in HepG2 cells. 5. Taken together, the decreased carboxylesterases expression and hydrolytic activity in T2D mice are through the Akt/mTOR/HIF-1α/Stra13 (DEC1) pathway.

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Insulin Promotes Glucose Consumption via Regulation of miR-99a/mTOR/PKM2 Pathway

Cited by 35 publications

References 53 publications

Mammalian target of rapamycin controls glucose consumption and redox balance in human Sertoli cells

Mammalian target of rapamycin controls glucose consumption and redox balance in human Sertoli cells

microRNA-99a Reduces Lipopolysaccharide-Induced Oxidative Injury by Activating Notch Pathway in H9c2 Cells

Decreased carboxylesterases expression and hydrolytic activity in type 2 diabetic mice through Akt/mTOR/HIF-1α/Stra13 pathway

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