Table_1_Extracellular ATP Increases Glucose Metabolism in Skeletal Muscle Cells in a P2 Receptor Dependent Manner but Does Not Contribute to Palmitate-Induced Insulin Resistance.docx
Saturated fatty acids such as palmitate contribute to the development of Type 2 Diabetes by reducing insulin sensitivity, increasing inflammation and potentially contributing to anabolic resistance. We hypothesized that palmitate-induced ATP release from skeletal muscle cells may increase inflammatory cytokine production and contribute to insulin/anabolic resistance in an autocrine/paracrine manner. In C2C12 myotubes differentiated at physiological glucose concentrations (5.5 mM), palmitate treatment (16 h) at concentrations greater than 250 μM increased release of ATP and inflammatory cytokines IL-6 and MIF, significantly blunted insulin and amino acid-induced signaling and reduced mitochondrial function. In contrast to our hypothesis, degradation of extracellular ATP using apyrase, did not alter palmitate-induced insulin resistance nor alter release of cytokines. Moreover, treatment with ATPγS (16 h), a non-hydrolysable ATP analog, in the absence of palmitate, did not diminish insulin sensitivity. Acute treatment with ATPγS produced insulin mimetic roles; increased phosphorylation of PKB (aka AKT), S6K1 and ERK and enhanced GLUT4-mediated glucose uptake in the absence of exogenous insulin. The increases in PKB and S6K1 phosphorylation were completely prevented by pre-incubation with broad spectrum purinergic receptor (P2R) blockers PPADs and suramin but not by P2 × 4 or P2 × 7 blockers 5-BDBD or A-438079, respectively. Moreover, ATPγS increased IL-6 yet decreased MIF release, similar to the cytokine profile produced by exercise. Acute and chronic treatment with ATPγS increased glycolytic rate in a manner that was differentially inhibited by PPADs and suramin, suggesting heterogeneous P2R activation in the control of cellular metabolism. In summary, our data suggest that the palmitate-induced increase in ATP does not contribute to insulin/anabolic resistance in a cell autonomous manner.
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References
- https://doi.org//10.1096/fj.14-255901
- https://doi.org//10.1016/j.metabol.2007.10.009
- https://doi.org//10.4049/jimmunol.179.8.5399
- https://doi.org//10.1038/ncprheum0701
- https://doi.org//10.3945/ajcn.116.130385
- https://doi.org//10.2337/dbi18-0042
- https://doi.org//10.1016/s1043-4666(03)00076-0
- https://doi.org//10.1111/j.1748-1716.2011.02373.x
- https://doi.org//10.1074/jbc.m109.057315
- https://doi.org//10.2337/db05-1404
- https://doi.org//10.1371/journal.pone.0036916
- https://doi.org//10.1007/s00424-001-0757-x
- https://doi.org//10.1210/jc.2004-0436
- https://doi.org//10.12965/jer.1836256.128
- https://doi.org//10.3389/fimmu.2014.00580
- https://doi.org//10.1111/apha.12200
- https://doi.org//10.1007/s00125-014-3224-x
- https://doi.org//10.2337/db07-1265
- https://doi.org//10.1152/jappl.1993.75.2.712
- https://doi.org//10.1210/jc.2008-2216
- https://doi.org//10.1016/j.bbrc.2016.03.159
- https://doi.org//10.2337/diabetes.51.7.2005
- https://doi.org//10.3390/ijms19092804
- https://doi.org//10.1186/1550-2783-11-28
- https://doi.org//10.1210/en.2004-1560
- https://doi.org//10.2337/diabetes.32.7.675
- https://doi.org//10.1371/journal.pone.0127919
- https://doi.org//10.1038/ijo.2015.104
- https://doi.org//10.1152/ajpcell.00250.2016
- https://doi.org//10.1523/jneurosci.20-14-05292.2000
- https://doi.org//10.1007/s11010-011-0726-4
- https://doi.org//10.1113/jphysiol.2012.238576
- https://doi.org//10.1016/j.bbrc.2014.01.089
- https://doi.org//10.1152/japplphysiol.00638.2009
- https://doi.org//10.2337/db15-0021
- https://doi.org//10.2337/db12-1066
- https://doi.org//10.1152/physrev.90100.2007
- https://doi.org//10.1152/ajpendo.00617.2005
- https://doi.org//10.1152/physrev.00063.2017
- https://doi.org//10.2337/db14-0150
- https://doi.org//10.1001/jama.286.3.327
- https://doi.org//10.1113/jphysiol.2008.155432
- https://doi.org//10.1074/jbc.C200444200
- https://doi.org//10.1038/icb.2011.89
- https://doi.org//10.3389/fphys.2019.00532
- https://doi.org//10.1152/ajprenal.00325.2009
- https://doi.org//10.1111/j.1469-7793.2000.00237.x
- https://doi.org//10.2337/db14-0961
- https://doi.org//10.1016/j.plipres.2005.11.002
- https://doi.org//10.2337/db09-1068
- https://doi.org//10.3389/fphar.2017.00878
- https://doi.org//10.1016/j.jbspin.2018.07.001
- https://doi.org//10.1111/dom.12912
- https://doi.org//10.1371/journal.pone.0096024
- https://doi.org//10.1210/clinem/dgaa184
- https://doi.org//10.1186/1743-7075-10-57
- https://doi.org//10.1152/ajpendo.00328.2010
- https://doi.org//10.1172/JCI88880
- https://doi.org//10.1152/ajpcell.00175.2012
- https://doi.org//10.2337/diacare.23.2.256
- https://doi.org//10.1155/2018/4081802