Prenylflavonoids from fruit of Macaranga tanarius promote glucose uptake via AMPK activation in L6 myotubes

Root extracts of a Cameroon medicinal plant, Dorstenia psilurus, were purified by screening for AMP-activated protein kinase (AMPK) activation in incubated mouse embryo fibroblasts (MEFs). Two isoprenylated flavones that activated AMPK were isolated. Compound 1 was identified as artelasticin by high-resolution electrospray ionization mass spectrometry and 2D-NMR while its structural isomer, compound 2, was isolated for the first time and differed only by the position of one double bond on one isoprenyl substituent. Treatment of MEFs with purified compound 1 or compound 2 led to rapid and robust AMPK activation at low micromolar concentrations and increased the intracellular AMP:ATP ratio. In oxygen consumption experiments on isolated rat liver mitochondria, compound 1 and compound 2 inhibited complex II of the electron transport chain and in freeze–thawed mitochondria succinate dehydrogenase was inhibited. In incubated rat skeletal muscles, both compounds activated AMPK and stimulated glucose uptake. Moreover, these effects were lost in muscles pre-incubated with AMPK inhibitor SBI-0206965, suggesting AMPK dependency. Incubation of mouse hepatocytes with compound 1 or compound 2 led to AMPK activation, but glucose production was decreased in hepatocytes from both wild-type and AMPKβ1−/− mice, suggesting that this effect was not AMPK-dependent. However, when administered intraperitoneally to high-fat diet-induced insulin-resistant mice, compound 1 and compound 2 had blood glucose-lowering effects. In addition, compound 1 and compound 2 reduced the viability of several human cancer cells in culture. The flavonoids we have identified could be a starting point for the development of new drugs to treat type 2 diabetes.

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Peptide Analogues of VPP and IPP with Improved Glucose Uptake Activity in L6 Myotubes can be Released from Cereal Proteins

Journal of Agricultural and Food Chemistry ◽

10.1021/acs.jafc.1c00587 ◽

2021 ◽

Author(s):

Ling Liu ◽

Jiexia Zheng ◽

Mengjie Zhou ◽

Shanshan Li ◽

Guoqing He ◽

...

Keyword(s):

Glucose Uptake ◽

L6 Myotubes ◽

Uptake Activity ◽

Peptide Analogues ◽

Cereal Proteins

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In vitro glucose uptake activity of Aegles marmelos and Syzygium cumini by activation of Glut-4, PI3 kinase and PPARγ in L6 myotubes

Phytomedicine ◽

10.1016/j.phymed.2005.03.008 ◽

2006 ◽

Vol 13 (6) ◽

pp. 434-441 ◽

Cited By ~ 53

Author(s):

R. Anandharajan ◽

S. Jaiganesh ◽

N.P. Shankernarayanan ◽

R.A. Viswakarma ◽

A. Balakrishnan

Keyword(s):

Glucose Uptake ◽

Pi3 Kinase ◽

Syzygium Cumini ◽

Glut 4 ◽

L6 Myotubes ◽

Uptake Activity

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Anti-Prediabetic Effect of 6-O-Caffeoylsophorose in Prediabetic Rats and Its Stimulation of Glucose Uptake in L6 Myotubes

Food Science and Technology Research ◽

10.3136/fstr.23.449 ◽

2017 ◽

Vol 23 (3) ◽

pp. 449-456 ◽

Cited By ~ 2

Author(s):

Gonzalo Miyagusuku-Cruzado ◽

Naoki Morishita ◽

Keiichi Fukui ◽

Norihiko Terahara ◽

Toshiro Matsui

Keyword(s):

Glucose Uptake ◽

L6 Myotubes ◽

Stimulation Of

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Gingerols of Zingiber officinale Enhance Glucose Uptake by Increasing Cell Surface GLUT4 in Cultured L6 Myotubes

Planta Medica ◽

10.1055/s-0032-1315041 ◽

2012 ◽

Vol 78 (14) ◽

pp. 1549-1555 ◽

Cited By ~ 48

Author(s):

Yiming Li ◽

Van Tran ◽

Colin Duke ◽

Basil Roufogalis

Keyword(s):

Cell Surface ◽

Glucose Uptake ◽

Zingiber Officinale ◽

L6 Myotubes

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Abstract 158: A Tether Containing a UBX Domain (TUG) Mediates Glucose Transporter Translocation in the Ischemic Heart

Circulation Research ◽

10.1161/res.121.suppl_1.158 ◽

2017 ◽

Vol 121 (suppl_1) ◽

Author(s):

Ji Li ◽

Yina Ma ◽

Jonathan Bogan

Keyword(s):

Cell Surface ◽

Glucose Uptake ◽

Glucose Transporter ◽

Ex Vivo ◽

Ischemia And Reperfusion ◽

Ampk Activation ◽

Glut4 Translocation ◽

Heart Perfusion ◽

Intracellular Vesicles

Introduction: The adaptive metabolic regulation of glucose and fatty acid in the heart plays a critical role in limiting cardiac damage caused by ischemia and reperfusion (I/R). TUG (tether containing a UBX domain, for GLUT4) can be cleaved to mobilize glucose transporter GLUT4 from intracellular vesicles to the cell surface in skeletal muscle and adipose in response to insulin stimulation. The energy sensor AMP-activated protein kinase (AMPK) plays an important cardioprotective role in response to ischemic insults by modulating GLUT4 translocation. Hypothesis: TUG is one of the downstream targets of AMPK in the heart. TUG could be phosphorylated by ischemic AMPK and cleaved to dissociate with GLUT4 and increase GLUT4 translocation in the ischemic heart. Methods: In vivo regional ischemia by ligation of left anterior coronary artery and ex vivo isolated mouse heart perfusion Langendorff system were used to test the hypothesis. Results: Antithrombin (AT) is an endogenous AMPK agonist in the heart and used to define the role of TUG in regulating GLUT4 trafficking during ischemia and reperfusion in the heart. AT showed its cardioprotective function through recovering cardiac pumping function and activating AMPK. The results showed that AMPK activation by AT treatment was through LKB1 and Sesn2 complex. Furthermore, the ex vivo heart perfusion data demonstrated that AT administration significantly increase GLUT4 translocation, glucose uptake, glycolysis and glucose oxidation during ischemia and reperfusion (p<0.05 vs . vehicle). Moreover, AT treatment increased abundance of a TUG cleavage product (42 KD) in response to I/R. The TUG protein was clearly phosphorylated by activated AMPK in HL-1 cardiomyocytes. The in vivo myocardial ischemia results demonstrated that ischemic AMPK activation triggers TUG cleavage and significantly increases GLUT4 translocation to the cell surface. Moreover, an augmented interaction between AMPK and TUG was observed during ischemia. Conclusions: Cardiac AMPK activation stimulates TUG cleavage and causes the dissociation between TUG and GLUT4 in the intracellular vesicles. TUG is a critical mediator that modulates cardiac GLUT4 translocation to cell surface and enhances glucose uptake by AMPK signaling pathway.

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Saturated, but not n-6 polyunsaturated, fatty acids induce insulin resistance: role of intramuscular accumulation of lipid metabolites

Journal of Applied Physiology ◽

10.1152/japplphysiol.01438.2005 ◽

2006 ◽

Vol 100 (5) ◽

pp. 1467-1474 ◽

Cited By ~ 203

Author(s):

Jong Sam Lee ◽

Srijan K. Pinnamaneni ◽

Su Ju Eo ◽

In Ho Cho ◽

Jae Hwan Pyo ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Fatty Acids ◽

Insulin Sensitivity ◽

Polyunsaturated Fatty Acids ◽

Glucose Uptake ◽

High Fat ◽

Insulin Resistant ◽

L6 Myotubes ◽

Lipid Metabolites

Consumption of a Western diet rich in saturated fats is associated with obesity and insulin resistance. In some insulin-resistant phenotypes this is associated with accumulation of skeletal muscle fatty acids. We examined the effects of diets high in saturated fatty acids (Sat) or n-6 polyunsaturated fatty acids (PUFA) on skeletal muscle fatty acid metabolite accumulation and whole-body insulin sensitivity. Male Sprague-Dawley rats were fed a chow diet (16% calories from fat, Con) or a diet high (53%) in Sat or PUFA for 8 wk. Insulin sensitivity was assessed by fasting plasma glucose and insulin and glucose tolerance via an oral glucose tolerance test. Muscle ceramide and diacylglycerol (DAG) levels and triacylglycerol (TAG) fatty acids were also measured. Both high-fat diets increased plasma free fatty acid levels by 30%. Compared with Con, Sat-fed rats were insulin resistant, whereas PUFA-treated rats showed improved insulin sensitivity. Sat caused a 125% increase in muscle DAG and a small increase in TAG. Although PUFA also resulted in a small increase in DAG, the excess fatty acids were primarily directed toward TAG storage (105% above Con). Ceramide content was unaffected by either high-fat diet. To examine the effects of fatty acids on cellular lipid storage and glucose uptake in vitro, rat L6 myotubes were incubated for 5 h with saturated and polyunsaturated fatty acids. After treatment of L6 myotubes with palmitate (C16:0), the ceramide and DAG content were increased by two- and fivefold, respectively, concomitant with reduced insulin-stimulated glucose uptake. In contrast, treatment of these cells with linoleate (C18:2) did not alter DAG, ceramide levels, and glucose uptake compared with controls (no added fatty acids). Both 16:0 and 18:2 treatments increased myotube TAG levels (C18:2 vs. C16:0, P < 0.05). These results indicate that increasing dietary Sat induces insulin resistance with concomitant increases in muscle DAG. Diets rich in n-6 PUFA appear to prevent insulin resistance by directing fat into TAG, rather than other lipid metabolites.

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Insulin sensitivity is inversely related to cellular energy status, as revealed by biotin deprivation

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00442.2013 ◽

2014 ◽

Vol 306 (12) ◽

pp. E1442-E1448 ◽

Cited By ~ 2

Author(s):

Ana Salvador-Adriano ◽

Sonia Vargas-Chávez ◽

Alain de J. Hernández-Vázquez ◽

Daniel Ortega-Cuellar ◽

Armando R. Tovar ◽

...

Keyword(s):

Insulin Sensitivity ◽

Glucose Uptake ◽

Muscle Cells ◽

Independent Effect ◽

Ampk Activation ◽

Energy Status ◽

Biotin Deficiency ◽

Deficient Diet ◽

Insulin Tolerance

We have reported an early decrease in glycemia in rats fed a biotin-deficient diet with reduced cellular ATP levels, suggesting increased insulin sensitivity. Here, we show that biotin-deprived rats are more tolerant of glucose, as shown by both oral and intraperitoneal glucose tolerance tests, during which insulin plasma levels were significantly diminished in deficient rats compared with controls. Biotin-deficient rats had lower blood glucose concentrations during intraperitoneal insulin sensitivity tests than controls. Furthermore, more glucose was infused to maintain euglycemia in the biotin-deficient rats during hyperinsulinemic euglycemic clamp studies. These results demonstrate augmented sensitivity to insulin in biotin-deprived rats. They are most likely the consequence of an insulin-independent effect of AMPK activation on GLUT4 membrane translocation with increased glucose uptake. In biotin-deficient cultured L6 muscle cells, there was increased phosphorylation of the energy sensor AMPK. We have now confirmed the augmented AMPK activation in both biotin-deprived in vivo muscle and cultured muscle cells. In these cells, glucose uptake is increased by AMPK activation by AICAR and diminished by its knockdown by the specific siRNAs directed against its α1- and α2-catalytic subunits, with all of these effects being largely independent of the activity of the insulin-signaling pathway that was inhibited with wortmannin. The enhanced insulin sensitivity in biotin deficiency likely has adaptive value for organisms due to the hormone promotion of uptake and utilization of not only glucose but other nutrients such as branched-chain amino acids, whose deficiency has been reported to increase insulin tolerance.

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Attenuation of Free Fatty Acid-Induced Muscle Insulin Resistance by Rosemary Extract

Nutrients ◽

10.3390/nu10111623 ◽

2018 ◽

Vol 10 (11) ◽

pp. 1623 ◽

Cited By ~ 6

Author(s):

Filip Vlavcheski ◽

Evangelia Tsiani

Keyword(s):

Insulin Resistance ◽

Glucose Uptake ◽

Muscle Cell ◽

Serine Phosphorylation ◽

Rosemary Extract ◽

Muscle Insulin Resistance ◽

Insulin Resistant ◽

L6 Myotubes ◽

P70 S6k ◽

Amp Activated Protein Kinase

Elevated blood free fatty acids (FFAs), as seen in obesity, impair muscle insulin action leading to insulin resistance and Type 2 diabetes mellitus. Serine phosphorylation of the insulin receptor substrate (IRS) is linked to insulin resistance and a number of serine/threonine kinases including JNK, mTOR and p70 S6K have been implicated in this process. Activation of the energy sensor AMP-activated protein kinase (AMPK) increases muscle glucose uptake, and in recent years AMPK has been viewed as an important target to counteract insulin resistance. We reported recently that rosemary extract (RE) increased muscle cell glucose uptake and activated AMPK. However, the effect of RE on FFA-induced muscle insulin resistance has never been examined. In the current study, we investigated the effect of RE in palmitate-induced insulin resistant L6 myotubes. Exposure of myotubes to palmitate reduced the insulin-stimulated glucose uptake, increased serine phosphorylation of IRS-1, and decreased the insulin-stimulated phosphorylation of Akt. Importantly, exposure to RE abolished these effects and the insulin-stimulated glucose uptake was restored. Treatment with palmitate increased the phosphorylation/activation of JNK, mTOR and p70 S6K whereas RE completely abolished these effects. RE increased the phosphorylation of AMPK even in the presence of palmitate. Our data indicate that rosemary extract has the potential to counteract the palmitate-induced muscle cell insulin resistance and further studies are required to explore its antidiabetic properties.

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