PMID- 32664532
OWN - NLM
STAT- MEDLINE
DCOM- 20210222
LR  - 20211204
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 21
IP  - 14
DP  - 2020 Jul 11
TI  - Attenuation of Free Fatty Acid (FFA)-Induced Skeletal Muscle Cell Insulin 
      Resistance by Resveratrol is Linked to Activation of AMPK and Inhibition of mTOR 
      and p70 S6K.
LID - 10.3390/ijms21144900 [doi]
LID - 4900
AB  - Insulin resistance, a main characteristic of type 2 diabetes mellitus (T2DM), is 
      linked to obesity and excessive levels of plasma free fatty acids (FFA). Studies 
      indicated that significantly elevated levels of FFAs lead to skeletal muscle 
      insulin resistance, by dysregulating the steps in the insulin signaling cascade. 
      The polyphenol resveratrol (RSV) was shown to have antidiabetic properties but 
      the exact mechanism(s) involved are not clearly understood. In the present study, 
      we examined the effect of RSV on FFA-induced insulin resistance in skeletal 
      muscle cells in vitro and investigated the mechanisms involved. Parental and 
      GLUT4myc-overexpressing L6 rat skeletal myotubes were used. [(3)H]2-deoxyglucose 
      (2DG) uptake was measured, and total and phosphorylated levels of specific 
      proteins were examined by immunoblotting. Exposure of L6 cells to FFA palmitate 
      decreased the insulin-stimulated glucose uptake, indicating insulin resistance. 
      Palmitate increased ser(307) (131% +/- 1.84% of control, p < 0.001) and 
      ser(636/639) (148% +/- 10.1% of control, p < 0.01) phosphorylation of IRS-1, and 
      increased the phosphorylation levels of mTOR (174% +/- 15.4% of control, p < 0.01) 
      and p70 S6K (162% +/- 20.2% of control, p < 0.05). Treatment with RSV completely 
      abolished these palmitate-induced responses. In addition, RSV increased the 
      activation of AMPK and restored the insulin-mediated increase in (a) plasma 
      membrane GLUT4 glucose transporter levels and (b) glucose uptake. These data 
      suggest that RSV has the potential to counteract the FFA-induced muscle insulin 
      resistance.
FAU - Den Hartogh, Danja J
AU  - Den Hartogh DJ
AD  - Department of Health Sciences, Brock University, St. Catharines, ON L2S 3A1, 
      Canada.
AD  - Centre for Bone and Muscle Health, Brock University, St. Catharines, ON L2S 3A1, 
      Canada.
FAU - Vlavcheski, Filip
AU  - Vlavcheski F
AUID- ORCID: 0000-0001-9615-1775
AD  - Department of Health Sciences, Brock University, St. Catharines, ON L2S 3A1, 
      Canada.
AD  - Centre for Bone and Muscle Health, Brock University, St. Catharines, ON L2S 3A1, 
      Canada.
FAU - Giacca, Adria
AU  - Giacca A
AD  - Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
AD  - Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
AD  - Institute of Medical Sciences, University of Toronto, Toronto, ON M5S 1A8, 
      Canada.
AD  - Banting and Best Diabetes Centre, University of Toronto, Toronto, ON M5G 2C4, 
      Canada.
FAU - Tsiani, Evangelia
AU  - Tsiani E
AUID- ORCID: 0000-0003-4218-5851
AD  - Department of Health Sciences, Brock University, St. Catharines, ON L2S 3A1, 
      Canada.
AD  - Centre for Bone and Muscle Health, Brock University, St. Catharines, ON L2S 3A1, 
      Canada.
LA  - eng
PT  - Journal Article
DEP - 20200711
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Fatty Acids, Nonesterified)
RN  - 0 (Glucose Transporter Type 4)
RN  - 0 (Insulin Receptor Substrate Proteins)
RN  - 0 (Irs1 protein, rat)
RN  - 0 (Palmitates)
RN  - 0 (Slc2a4 protein, rat)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.4.3 (Adenylate Kinase)
RN  - IY9XDZ35W2 (Glucose)
RN  - Q369O8926L (Resveratrol)
SB  - IM
MH  - Adenylate Kinase/*physiology
MH  - Animals
MH  - Cell Line
MH  - Fatty Acids, Nonesterified/*toxicity
MH  - Glucose/metabolism
MH  - Glucose Transporter Type 4/metabolism
MH  - Humans
MH  - Insulin Receptor Substrate Proteins/metabolism
MH  - Insulin Resistance/*physiology
MH  - Muscle Cells/drug effects/metabolism
MH  - Muscle, Skeletal/*drug effects/metabolism
MH  - Palmitates/pharmacology/toxicity
MH  - Phosphorylation
MH  - Protein Processing, Post-Translational/drug effects
MH  - Protein Transport/drug effects
MH  - Rats
MH  - Resveratrol/*pharmacology
MH  - Ribosomal Protein S6 Kinases, 70-kDa/*physiology
MH  - Signal Transduction/drug effects
MH  - TOR Serine-Threonine Kinases/*physiology
PMC - PMC7404286
OTO - NOTNLM
OT  - AMPK
OT  - Akt
OT  - GLUT4
OT  - IRS-1
OT  - free fatty acid
OT  - insulin resistance
OT  - mTOR
OT  - p70 S6K
OT  - palmitate
OT  - resveratrol
COIS- The authors declare no conflict of interest.
EDAT- 2020/07/16 06:00
MHDA- 2021/02/23 06:00
PMCR- 2020/07/01
CRDT- 2020/07/16 06:00
PHST- 2020/05/24 00:00 [received]
PHST- 2020/07/03 00:00 [revised]
PHST- 2020/07/09 00:00 [accepted]
PHST- 2020/07/16 06:00 [entrez]
PHST- 2020/07/16 06:00 [pubmed]
PHST- 2021/02/23 06:00 [medline]
PHST- 2020/07/01 00:00 [pmc-release]
AID - ijms21144900 [pii]
AID - ijms-21-04900 [pii]
AID - 10.3390/ijms21144900 [doi]
PST - epublish
SO  - Int J Mol Sci. 2020 Jul 11;21(14):4900. doi: 10.3390/ijms21144900.