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

Abstract

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. [3H]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 ser307 (131% ± 1.84% of control, p < 0.001) and ser636/639 (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.

Resveratrol, Metabolic Dysregulation, and Alzheimer’s Disease: Considerations for Neurogenerative Disease

“…Alongside the importance of the SIRT1/AMPK interaction, RSV has also been shown to activate AMPK directly to exert a key set of metabolic benefits: improving mitochondrial content/function (increased PGC1- content, increased activity of COXIV, and citrate synthase), improvements in insulin sensitivity and glucose uptake (increased GLUT4 translocation, reduced IGF-I, improved Akt signaling), increased autophagic/mitophagic clearance of cell debris, and increased FFA mobilization (increased PDH, PDK4, ATGL content) [ 94 , 95 , 96 , 97 , 98 , 99 ]. These metabolic alterations are well documented to occur in several peripheral tissues including skeletal muscle, liver, heart, and adipose tissue and have all been directly related to improvements in T2D and obesity pathology [ 97 , 98 , 99 , 100 , 101 ]. Activation by RSV occurs directly through AMPKs upstream kinases, LKB1 and CAMKK , but also indirectly by modifying the AMP/ATP ratio through impairing ATP production by the inhibition of mitochondrial complex V (F 1 F 0 -ATPase/ATP synthase) [ 68 , 102 ].…”

“…[ 96 ]. As well, most research, showing RSV-meditated improvements/prevention on metabolic syndrome through SIRT1 or AMPK, has been thoroughly demonstrated in peripheral tissues rather than the brain [ 68 , 93 , 96 , 99 , 102 , 106 , 120 , 121 ]. As such, the evidence supporting the role of RSV in mitigating metabolic syndrome in the brain and regulating AD pathology is promising, particularly in the case of Qi et al [ 115 ].…”

Protective Effect of Jiang Tang Xiao Ke Granules against Skeletal Muscle IR via Activation of the AMPK/SIRT1/PGC‐1α Signaling Pathway

“…Although the exact mechanism that leads to the development of IR in skeletal muscle is not yet fully understood, accumulation of glucose and FFA have been shown to play a primary role [ 25 , 26 ]. In the current study, we observed impaired glucose tolerance and abnormal lipid profiles in diabetic mice.…”

Resveratrol improves skeletal muscle insulin resistance through downregulating lncRNA NONMMUT044897.2

“…Several studies have indicated RSV possesses a satisfying anti-insulin resistance activity in skeletal muscle [8,9,10]. It is related to the activation of 5-adenosine monophosphate-activated protein kinase and restoration of glucose transporter 4 translocations [8,9]. Our earlier research also proved that skeletal muscle insulin resistance caused by a high-fat diet may be alleviated after RSV treatment [10].…”

“…Accumulating evidence has indicated that RSV displayed a diversity of biological activities [4,5], including anti-oxidative, anti-aging, anti-in ammatory, hypoglycemic property, and attenuate insulin resistance [6,7]. Several studies have indicated RSV possesses a satisfying anti-insulin resistance activity in skeletal muscle [8,9,10]. It is related to the activation of 5-adenosine monophosphate-activated protein kinase and restoration of glucose transporter 4 translocations [8,9].…”