Pentadecanoic acid promotes basal and insulin-stimulated glucose uptake in C2C12 myotubes

A series of clinical trials and animal experiments have demonstrated that ginseng and its major active constituent, ginsenosides, possess glucose-lowering action. In our previous study, ginsenoside Rb1 has been shown to regulate peroxisome proliferator-activated receptor γ activity to facilitate adipogenesis of 3T3-L1 cells. However, the effect of Rb1 on glucose transport in insulin-sensitive cells and its molecular mechanism need further elucidation. In this study, Rb1 significantly stimulated basal and insulin-mediated glucose uptake in a time- and dose-dependent manner in 3T3-L1 adipocytes and C2C12 myotubes; the maximal effect was achieved at a concentration of 1 μM and a time of 3 h. In adipocytes, Rb1 promoted GLUT1 and GLUT4 translocations to the cell surface, which was examined by analyzing their distribution in subcellular membrane fractions, and enhanced translocation of GLUT4 was confirmed using the transfection of GLUT4-green fluorescence protein in Chinese Hamster Ovary cells. Meanwhile, Rb1 increased the phosphorylation of insulin receptor substrate-1 and protein kinase B (PKB), and stimulated phosphatidylinositol 3-kinase (PI3K) activity in the absence of the activation of the insulin receptor. Rb1-induced glucose uptake as well as GLUT1 and GLUT4 translocations was inhibited by the PI3K inhibitor. These results suggest that ginsenoside Rb1 stimulates glucose transport in insulin-sensitive cells by promoting translocations of GLUT1 and GLUT4 by partially activating the insulin signaling pathway. These findings are useful in understanding the hypoglycemic and anti-diabetic properties of ginseng and ginsenosides.

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The Effects of Propionate and Valerate on Insulin Responsiveness for Glucose Uptake in 3T3-L1 Adipocytes and C2C12 Myotubes via G Protein-Coupled Receptor 41

PLoS ONE ◽

10.1371/journal.pone.0095268 ◽

2014 ◽

Vol 9 (4) ◽

pp. e95268 ◽

Cited By ~ 24

Author(s):

Joo-Hui Han ◽

In-Su Kim ◽

Sang-Hyuk Jung ◽

Sang-Gil Lee ◽

Hwa-Young Son ◽

...

Keyword(s):

Glucose Uptake ◽

G Protein ◽

C2c12 Myotubes ◽

G Protein Coupled Receptor ◽

Insulin Responsiveness ◽

G Protein Coupled

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14-Deoxy-11,12-Didehydroandrographolide Ameliorates Glucose Intolerance Enhancing the LKB1/AMPKα/TBC1D1/GLUT4 Signaling Pathway and Inducing GLUT4 Expression in Myotubes and Skeletal Muscle of Obese Mice

The American Journal of Chinese Medicine ◽

10.1142/s0192415x21500695 ◽

2021 ◽

pp. 1-19

Author(s):

Chih-Chieh Chen ◽

Chong-Kuei Lii ◽

Chia-Wen Lo ◽

Yi-Hsueh Lin ◽

Ya-Chen Yang ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Glucose Uptake ◽

Signaling Pathway ◽

Nuclear Translocation ◽

Time Dependent ◽

Antidiabetic Activity ◽

C2c12 Myotubes ◽

Dependent Manner ◽

Compound C

14-Deoxy-11,12-didehydroandrographolide (deAND), a bioactive component of Andrographis paniculata, has antidiabetic activity. AMP-activated protein kinase (AMPK) regulates glucose transport and ameliorates insulin resistance. The aim of the present study was to investigate whether activation of AMPK is involved in the mechanism by which deAND ameliorates insulin resistance in muscles. deAND amounts up to 40 [Formula: see text]M dose-dependently activated phosphorylation of AMPK[Formula: see text] and TBC1D1 in C2C12 myotubes. In addition, deAND significantly activated phosphorylation of LKB1 at 6 h after treatment, and this activation was maintained up to 48 h. deAND increased glucose uptake at 18 h after treatment, and this increase was time dependent up to 72 h. Compound C, an inhibitor of AMPK, suppressed deAND-induced phosphorylation of AMPK[Formula: see text] and TBC1D1 and reversed the effect on glucose uptake. In addition, the expression of GLUT4 mRNA and protein in C2C12 myotubes was up-regulated by deAND in a time-dependent manner. Promotion of GLUT4 gene transcription was verified by a pGL3-GLUT4 (837 bp) reporter assay. deAND also increased the nuclear translocation of MEF-2A and PPAR[Formula: see text]. After 16 weeks of feeding, the high-fat diet (HFD) inhibited phosphorylation of AMPK[Formula: see text] and TBC1D1 in skeletal muscle of obese C57BL/6JNarl mice, and deactivation of AMPK[Formula: see text] and TBC1D1 by the HFD was abolished by deAND supplementation. Supplementation with deAND significantly promoted membrane translocation of GLUT4 compared with the HFD group. Supplementation also significantly increased GLUT4 mRNA and protein expression in skeletal muscle compared with the HFD group. The hypoglycemic effects of deAND are likely associated with activation of the LKB1/AMPK[Formula: see text]/TBC1D1/GLUT4 signaling pathway and stimulation of MEF-2A- and PPAR[Formula: see text]-dependent GLUT4 gene expression, which account for the glucose uptake into skeletal muscle and lower blood glucose levels.

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Distinct effects of oleic acid and itstrans-isomer elaidic acid on the expression of myokines and adipokines in cell models

British Journal Of Nutrition ◽

10.1017/s0007114510004885 ◽

2011 ◽

Vol 105 (8) ◽

pp. 1226-1234 ◽

Cited By ~ 30

Author(s):

Nuria Granados ◽

Jaume Amengual ◽

Joan Ribot ◽

Andreu Palou ◽

M. Luisa Bonet

Keyword(s):

Gene Expression ◽

Fatty Acids ◽

Oleic Acid ◽

Insulin Sensitivity ◽

Glucose Uptake ◽

Elaidic Acid ◽

C2c12 Myotubes ◽

Cell Models ◽

Monounsaturated Fat ◽

Expression Levels

Trans-fatty acids (TFA) andcis-monounsaturated fat appear to exert detrimental and beneficial effects, respectively, on glucose metabolism and insulin sensitivity. Adipose tissue and skeletal muscle are a source of signalling proteins (adipokines and myokines), some of which have been related to the control of insulin sensitivity. Here, we investigated the possible differential effects of elaidic acid (EA;trans-9-18 : 1) – the major component in industrially produced TFA – and oleic acid (OA;cis-9-18 : 1) – itscis-isomer naturally present in food – on cellular glucose uptake and the expression of selected myokines and adipokines using cell models. Differentiated C2C12 myotubes and 3T3-L1 adipocytes were pretreated with the vehicle (control cells) or fatty acids for 24 h, after which basal and insulin-stimulated 2-deoxyglucose uptake and the expression of selected signalling proteins were measured. In C2C12 myotubes, pretreatment with OA, but not with EA, led to increased insulin-stimulated 2-deoxyglucose uptake and IL-6 expression levels, while pretreatment with EA, but not with OA, led to reduced IL-15 mRNA levels and increased TNF-α expression levels. In 3T3-L1 adipocytes, exposure to OA, but not to EA, resulted in reduced resistin gene expression and increased adiponectin gene expression. The results show evidence of distinct, direct effects of OA and EA on muscle glucose uptake and the expression of target myokines and adipokines, thus suggesting novel mechanisms by whichcis- andtrans-monounsaturated fat may differentially affect systemic functions.

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An AMPK/Axin1-Rac1 signaling pathway mediates contraction-regulated glucose uptake in skeletal muscle cells

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00272.2019 ◽

2020 ◽

Vol 318 (3) ◽

pp. E330-E342 ◽

Cited By ~ 3

Author(s):

Yingying Yue ◽

Chang Zhang ◽

Xuejiao Zhang ◽

Shitian Zhang ◽

Qian Liu ◽

...

Keyword(s):

Skeletal Muscle ◽

Glucose Uptake ◽

Signaling Pathway ◽

Gastrocnemius Muscle ◽

C2c12 Myotubes ◽

Dependent Manner ◽

Mouse Muscle ◽

Protein Levels ◽

Compound C ◽

Skeletal Muscle Glucose Uptake

Contraction stimulates skeletal muscle glucose uptake predominantly through activation of AMP-activated protein kinase (AMPK) and Rac1. However, the molecular details of how contraction activates these signaling proteins are not clear. Recently, Axin1 has been shown to form a complex with AMPK and liver kinase B1 during glucose starvation-dependent activation of AMPK. Here, we demonstrate that electrical pulse-stimulated (EPS) contraction of C2C12 myotubes or treadmill exercise of C57BL/6 mice enhanced reciprocal coimmunoprecipitation of Axin1 and AMPK from myotube lysates or gastrocnemius muscle tissue. Interestingly, EPS or exercise upregulated total cellular Axin1 levels in an AMPK-dependent manner in C2C12 myotubes and gastrocnemius mouse muscle, respectively. Also, direct activation of AMPK with 5-aminoimidazole-4-carboxamide ribonucleotide treatment of C2C12 myotubes or gastrocnemius muscle elevated Axin1 protein levels. On the other hand, siRNA-mediated Axin1 knockdown lessened activation of AMPK in contracted myotubes. Further, AMPK inhibition with compound C or siRNA-mediated knockdown of AMPK or Axin1 blocked contraction-induced GTP loading of Rac1, p21-activated kinase phosphorylation, and contraction-stimulated glucose uptake. In summary, our results suggest that an AMPK/Axin1-Rac1 signaling pathway mediates contraction-stimulated skeletal muscle glucose uptake.

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Transient Silencing of a Type IV P-Type ATPase,Atp10c, Results in Decreased Glucose Uptake in C2C12 Myotubes

Journal of Nutrition and Metabolism ◽

10.1155/2012/152902 ◽

2012 ◽

Vol 2012 ◽

pp. 1-9 ◽

Cited By ~ 6

Author(s):

S. E. Hurst ◽

S. C. Minkin ◽

J. Biggerstaff ◽

M. S. Dhar

Keyword(s):

Type 2 Diabetes ◽

Glucose Uptake ◽

Glucose Transporter ◽

Mapk Pathway ◽

Specific Inhibitor ◽

C2c12 Myotubes ◽

Glucose Transporter 1 ◽

Transfected Cells

Atp10cis a strong candidate gene for diet-induced obesity and type 2 diabetes. To identify molecular and cellular targets of ATP10C,Atp10cexpression was alteredin vitroin C2C12 skeletal muscle myotubes by transient transfection with anAtp10c-specific siRNA. Glucose uptake assays revealed that insulin stimulation caused a significant 2.54-fold decrease in 2-deoxyglucose uptake in transfected cells coupled with a significant upregulation of native mitogen-activated protein kinases (MAPKs), p38, and p44/42. Additionally, glucose transporter-1 (GLUT1) was significantly upregulated; no changes in glucose transporter-4 (GLUT4) expression were observed. The involvement of MAPKs was confirmed using the specific inhibitor SB203580, which downregulated the expression of native and phosphorylated MAPK proteins in transfected cells without any changes in insulin-stimulated glucose uptake. Results indicate thatAtp10cregulates glucose metabolism, at least in part via the MAPK pathway, and, thus, plays a significant role in the development of insulin resistance and type 2 diabetes.

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Sesquiterpenes from Baizhu Stimulate Glucose Uptake by Activating AMPK and PI3K

The American Journal of Chinese Medicine ◽

10.1142/s0192415x16500531 ◽

2016 ◽

Vol 44 (05) ◽

pp. 963-979 ◽

Cited By ~ 6

Author(s):

Chien-Liang Chao ◽

Hui-Chi Huang ◽

Hang-Ching Lin ◽

Tsu-Chung Chang ◽

Wen-Liang Chang

Keyword(s):

Glucose Uptake ◽

Herbal Medicines ◽

C2c12 Cells ◽

C2c12 Myotubes ◽

Insulin Mimetic ◽

Protein Levels ◽

Glut1 Protein ◽

Digestive Disorders ◽

Atractylodes Macrocephala ◽

Amp Activated Protein Kinase

Baizhu, the dried rhizome of Atractylodes Macrocephala Koidz (Compositae), is one of the most important traditional Chinese herbal medicines. Baizhu is generally used to treat digestive disorders and diabetes in Asian countries. This study investigates the activity of two sesquiterpenes isolated from Baizhu, atractylenolide I (AT-I) and atractylenolide II (AT-II), for their effects on glucose uptake in mouse skeletal muscle C2C12 cells, and the corresponding mechanism. These compounds show a significant stimulatory effect on glucose uptake in C2C12 myotubes. Both AT-I and AT-II significantly increased GLUT4 but not GLUT1 protein levels, and promoted GLUT4 translocation to the plasma membrane. The increased glucose uptake induced by these compounds is associated with activation of AMP-activated protein kinase (AMPK) and PI3K/Akt pathways in these cells. Further studies have indicated that AT-I and AT-II ameliorate TNF-[Formula: see text]-induced insulin resistance in C2C12 myotubes. In summary, our findings highlight the insulin mimetic activity of Baizhu in myotubes, and provide insights into the action mechanism underlying these effects. Our findings may also prove highly relevant to the development of novel therapeutic applications for these compounds.

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Chronic reactive oxygen species exposure inhibits glucose uptake and causes insulin resistance in C2C12 myotubes

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2016.08.028 ◽

2016 ◽

Vol 478 (2) ◽

pp. 798-803 ◽

Cited By ~ 18

Author(s):

Hongwen Ding ◽

Baoli Heng ◽

Wenfang He ◽

Liping Shi ◽

Caiyong Lai ◽

...

Keyword(s):

Insulin Resistance ◽

Reactive Oxygen Species ◽

Glucose Uptake ◽

Reactive Oxygen ◽

C2c12 Myotubes ◽

Oxygen Species

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Eleutheroside E, An Active Component ofEleutherococcus senticosus, Ameliorates Insulin Resistance in Type 2 Diabetic db/db Mice

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2013/934183 ◽

2013 ◽

Vol 2013 ◽

pp. 1-9 ◽

Cited By ~ 10

Author(s):

Jiyun Ahn ◽

Min Young Um ◽

Hyunjung Lee ◽

Chang Hwa Jung ◽

Seok Hyun Heo ◽

...

Keyword(s):

Insulin Resistance ◽

Glucose Uptake ◽

Serum Insulin ◽

Principal Component ◽

C2c12 Myotubes ◽

Protective Effects ◽

Beneficial Effects ◽

Eleutheroside E ◽

Type 2 Diabetic

Eleutheroside E (EE), a principal component ofEleutherococcus senticosus(ES), has anti-inflammatory and protective effects in ischemia heart. However, it is unknown whether it ameliorates insulin resistance and reduces hyperglycemia in diabetes. This study investigated the effect of EE-containing ES extracts, as well as EE, on hyperglycemia and insulin resistance in db/db mice. EE increased the insulin-provoked glucose uptake in C2C12 myotubes. Moreover, EE improved TNF-α-induced suppression of glucose uptake in 3T3-L1 adipocytes. Five-week-old db/db mice were fed a diet consisting of ES extract or EE for 5 weeks. Both were effective in improving serum lipid profiles and significantly decreased blood glucose and serum insulin levels. ES and EE supplementation effectively attenuated HOMA-IR. Glucose tolerance and insulin tolerance tests showed that EE increased insulin sensitivity. Immunohistochemical staining indicated that ES and EE protected pancreatic alpha and beta cells from diabetic damage. In addition, ES and EE improved hepatic glucose metabolism by upregulating glycolysis and downregulating gluconeogenesis in obese type 2 diabetic mice. These data suggest that EE mediates the hyperglycemic effects of ES by regulating insulin signaling and glucose utilization. The beneficial effects of EE may provide an effective and powerful strategy to alleviate diabetes.

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