Resveratrol, a polyphenol found in red wine, has been reported to have
antithrombotic, antiatherogenic, and anticancer properties both in vitro and III VIVO.
However, possible antidiabetic properties of resveratrol have not been examined. The
objective of this study was to investigate the direct effects of resveratrol on basal and
insulin-stimulated glucose uptake and to elucidate its mechanism of action in skeletal
muscle cells. In addition, the effects of resveratrol on basal and insulin- stimulated amino
acid transport and mitogenesis were also examined.
Fully differentiated L6 rat skeletal muscle cells were incubated with resveratrol
concentrations ranging from 1 to 250 IlM for 15 to 120 min. Maximum stimulation, 201
± 8.90% of untreated control, (p<0.001), of2eH] deoxy- D- glucose (2DG) uptake was
seen with 100 IlM resveratrol after 120 min. Acute, 30 min, exposure of the cells to 100
nM insulin stimulated 2DG uptake to 226 ± 12.52% of untreated control (p<0.001). This
appears to be a specific property of resveratrol that is not shared by structurally similar
antioxidants such as quercetin and rutin, both of which did not have any stimulatory
effect. Resveratrol increased the response of the cells to submaximal insulin
concentrations but did not alter the maximum insulin response. Resveratrol action did not
require insulin and was not blocked by the protein synthesis inhibitor cycloheximide.
L Y294002 and wortmannin, inhibitors of PI3K, abolished both insulin and resveratrolstimulated
glucose uptake while phosphorylation of AktlPKB, ERK1I2, JNK1I2, and p38
MAPK were not increased by resveratrol. Resveratrol did not stimulate GLUT4
transporter translocation in GLUT4cmyc overexpressing cells, in contrast to the
significant translocation observed with insulin. Furthermore, resveratrol- stimulated glucose transport was not blocked by the presence of the protein kinase C (PKC)
inhibitors BIMI and G06983. Despite that, resveratrol- induced glucose transport
required an intact actin network, similar to insulin.
In contrast to the stimulatory effect seen with resveratrol for glucose transport,
e4C]methylaminoisobutyric acid (MeAIB) transport was inhibited. Significant reduction
of MeAIB uptake was seen only with 100uM resveratrol (74.2 ± 6.55% of untreated
control, p<0.05), which appeared to be maximum. In parallel experiments, insulin (100
nM, 30 min) increased MeAIB transport by 147 ± 5.77% (p<0.00l) compared to
untreated control. In addition, resveratrol (100 JlM, 120 min) completely abolished
insulin- stimulated amino acid transport (103 ± 7.35% of untreated control,p>0.05).
Resveratrol also inhibited cell proliferation in L6 myoblasts with maximal
inhibition of eH]thymidine incorporation observed with resveratrol at 50 J.LM after 24
hours (8 ± 1.59% of untreated control, p<O.OOI). Insulin (100 nM, 24 h) significantly
increased thymidine incorporation (280 ± 9.92% of untreated control, p<O.OOI) and
media containing 10% FBS resulted in stimulation of thymidine incorporation to 691 ±
36.92% of untreated control, p<O.OO1. Resveratrol (50JlM) completely abolished both
insulin- (11 ± 1.26% of untreated control,p<O.OOI) and FBS- stimulated (36 ± 5.16% of
untreated control, p<0.05) cell proliferation.
These results suggest that resveratrol increases glucose transport in L6 skeletal
muscle cells by a mechanism that is in4ependent of insulin and protein synthesis.
Resveratrol- stimulated glucose uptake may be PI3K and actin cytoskeleton- dependent
and independent of AktIPKB, PKC, ERK1I2, JNK1I2, p38 MAPK, and GLUT4 translocation. However, unlike glucose transport, resveratrol inhibits both basal and insulin- stimulated amino acid transport and mitogenesis