Amelioration of High-Insulin-Induced Skeletal Muscle Cell Insulin Resistance by Resveratrol Is Linked to Activation of AMPK and Restoration of GLUT4 Translocation

Abstract

Insulin resistance, the hallmark of type 2 diabetes mellitus (T2DM), is linked to hyperinsulinemia, which develops to counterbalance initial peripheral hormone resistance. Studies indicate that chronically elevated levels of insulin lead to skeletal muscle insulin resistance by deregulating steps within the insulin signaling cascade. The polyphenol resveratrol (RSV) has been shown to have antidiabetic properties in vitro and in vivo. In the present study, we examined the effect of RSV on high insulin (HI)-induced insulin resistance in skeletal muscle cells in vitro and investigated the mechanisms involved. Parental and GLUT4myc-overexpressing L6 rat skeletal muscle cells 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 HI levels (100 nM) for 24 h decreased the acute-insulin-stimulated 2DG uptake, indicating insulin resistance. HI increased ser307 and ser636/639 phosphorylation of IRS-1 (to 184% ± 12% and 225% ± 28.9% of control, with p < 0.001 and p < 0.01, respectively) and increased the phosphorylation levels of mTOR (174% ± 6.7% of control, p < 0.01) and p70 S6K (228% ± 33.5% of control, p < 0.01). Treatment with RSV abolished these HI-induced responses. Furthermore, RSV increased the activation of AMPK and restored the insulin-mediated increase in plasma membrane GLUT4 glucose transporter levels. These data suggest that RSV has a potential to counteract the HI-induced muscle insulin resistance.

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

“…Previous studies performed in L6 muscle cells in vitro [ 8 , 29 , 37 ] and rat muscle tissue in vivo [ 38 ] indicated that increased serine (ser 307 and ser 636/639 ) phosphorylation of IRS-1 leads to impairments within the insulin signaling cascade, resulting in insulin resistance. Hence, we examined the effects of palmitate and RSV on serine phosphorylation and expression of IRS-1.…”

“…Phosphorylation/activation of AMPK in muscle cells was observed in response to contraction/exercise and exposure to chemicals that inhibit mitochondrial adenosine triphosphate (ATP) production, such as 2,4-dinitrophenol (DNP) [ 21 ]. Furthermore, there are several compounds that activate AMPK, including metformin [ 22 ], thiazolidineones [ 23 ], salicylate [ 24 ], and polyphenols, such as quercetin [ 25 ], berberine [ 26 ], and resveratrol [ 27 , 28 , 29 ]. Recently, AMPK activators have been considered to be a novel and attractive prophylactic or treatment strategy against insulin resistance and T2DM [ 30 ].…”

“…These effects of RSV were largely abolished in AMPK-α1 or -α2 knockout mice, indicating that AMPK plays a pivotal role in mediating the effects of RSV [ 34 ]. Additionally, we recently demonstrated that RSV ameliorated the high insulin-induced skeletal muscle cell insulin resistance, and that these effects were linked to AMPK activation/phosphorylation [ 29 ].…”

Disrupted circadian core-clock oscillations in Type 2 Diabetes are linked to altered rhythmic mitochondrial metabolism

“…Myotubes from T2D donors displayed fewer cycling rhythmic genes as compared to myotubes from NGT donors and the rhythmic genes in NGT were significantly associated with the rhythmic genes in T2D (Figure 1B, Fisher exact test, p=3.91e- 58). To induce acute insulin resistance and partly mimic a T2D milieu (Vlavcheski et al, 2020), myotubes from NGT and T2D donors were treated with high glucose and insulin (50 nM insulin, 25 mM glucose) for 24 hours prior to serum shock. High concentration glucose and insulin treatment reduced the number of cycling genes in myotubes from both T2D and NGT donors (Figure 1C).…”

The Study of the Response of Fat Metabolism to Long-Term Energy Stress Based on Serum, Fatty Acid and Transcriptome Profiles in Yaks

“…To achieve energy balance under long-term ES, yaks regulated fat metabolism by the expression of the downstream genes involved in AMPK signaling [ 49 ], as shown in Figure 4 . The expression of the SLC2A3 ( q < 0.05) and SLC2A4 ( q < 0.01) genes was downregulated in the subcutaneous fat of the yaks under ES, which indicated that less GLU from grass was translated into subcutaneous fat, and the muscles and organs could obtain limited GLU [ 50 ].…”