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-lipoic acid
1 Department of Molecular and Cell Biology and 3 Biological Technologies Section, Lawrence Berkeley National Laboratory, University of California, Berkeley, California 94720-3200; and 2 Department of Physiology, Faculty of Medicine, University of Kuopio, FIN 70211 Kuopio, Finland
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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In L6 myotubes, glucose uptake stimulated
by interferon (IFN)-
or lipopolysaccharides (LPS) and a combination
of LPS, IFN-, and tumor necrosis factor (TNF)-
was inhibited by
the antioxidant pyrrolidinedithiocarbamate and potentiated in reduced
glutathione (GSH)-deficient cells. Also, the stimulatory
effect of LPS and IFN- individually, and of a combination of LPS,
IFN-, and TNF-, on glucose uptake was associated with an
increased level of intracellular oxidants (dichlorofluorescein assay)
and loss of intracellular GSH. Study of the individual effects of LPS,
IFN-, and TNF- as well as of a combination of the three
activators provided evidence against a role of nitric oxide in
mediating the stimulatory effect of the above-mentioned agents on
glucose uptake. We also observed that the insulin-mimetic nutrient
-lipoic acid (LA; R-enantiomer) is able to stimulate glucose uptake
in cytokine-treated cells that are insulin resistant. This study shows
that cytokine-induced glucose uptake in skeletal muscle cells is redox
sensitive and that, under conditions of acute infection that is
accompanied with insulin resistance, LA may have therapeutic
implications in restoring glucose availability in tissues such as the
skeletal muscle.
antioxidant; immune system; infection; metabolism; nitric oxide; thioctic acid
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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CYTOKINES, THE SECRETORY products of macrophages, monocytes, and natural killer cells, have been suggested to mediate the effects of infection on glucose metabolism, particularly in the skeletal muscle (5-7, 21, 26, 46). In sepsis, for example, carbohydrate dyshomeostasis is a characteristic feature (4, 8, 13, 39, 40). Acute infection in sepsis is known to be associated with insulin resistance, as indicated by decreased glucose tolerance, hyperinsulinemia, and impaired insulin action on peripheral glucose disposal (38, 42). On the other hand, septic patients have an increased rate of basal glucose clearance (3, 25, 44). This response is thought to be cytokine mediated (5-7, 21, 26, 46).
The lymphokine interferon (IFN)- is known to influence glucose
metabolism (22). Cooperative action of tumor necrosis factor (TNF)-
and IFN- has been observed in the regulation of various cellular
responses, such as inducible nitric oxide (NO) production (1, 9).
Lipopolysaccharides (LPS), bacterial endotoxins that are known to
induce septic shock, may also enhance cellular glucose uptake (12, 25).
In sepsis, TNF-, IFN-, and LPS may directly stimulate cellular
glucose uptake but impair insulin regulation of peripheral glucose
disposal. A mechanism-based explanation of how cytokines influence
muscle glucose metabolism is currently lacking. Such information is
necessary to develop effective approaches to control irregularities in
glucose metabolism that is associated with infection. In a recent study
(1) in which the effect of a combination of TNF-, IFN-, and LPS
on glucose uptake by L6 myotubes was investigated, it was concluded
that cytokines modulate skeletal muscle glucose uptake by an
NO-dependent mechanism. In that work, however, the effect of individual
cytokines on muscle glucose uptake was not considered (1). In the
present study, we tested the hypothesis that cytokine-induced glucose
uptake in skeletal muscle cells is redox sensitive. To achieve this
goal, the effect of TNF-, IFN-, and LPS individually, as well as
in combination, on glucose uptake by L6 myotubes was investigated. Previous evidence suggests that cytokines confer insulin insensitivity to L6 myotubes (1). Thus we also sought to test whether the insulin-mimetic nutrient -lipoic acid (LA) would increase skeletal muscle glucose uptake in cytokine-treated cells that are known to be
insulin resistant. LA, or thioctic acid, is an effective modulator of
cellular redox status (29) that is known to stimulate skeletal muscle
glucose uptake by the favorable redistribution of glucose transporters
(10, 16). It has been successfully used clinically for the treatment of
diabetic polyneuropathies (2, 47, 48).
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MATERIALS AND METHODS |
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Materials
Rat thigh skeletal muscle-derived L6 cells, known to retain the morphological, metabolic, and biochemical characteristics of skeletal muscle (45), were obtained from American Type Culture Collection (Bethesda, MD). Dulbecco's phosphate-buffered saline (DPBS) and DMEM supplemented with high glucose, L-glutamine, pyridoxine hydrochloride, and 110 mg/l sodium pyruvate were obtained from GIBCO BRL (Life Technologies). Horse serum (HyClone Laboratories, Logan, UT), FCS, and other reagents for the culture medium were obtained from the cell culture facility of the University of California at San Francisco. Recombinant rat IFN- and TNF- were purchased from R & D Systems
(Minneapolis, MN). LPS isolated from
Escherichia coli,
L-buthionine-[S,R]-sulfoximine
(BSO), the ammonium salt of pyrrolidinedithiocarbamate (PDTC),
cytochalasin B, sulfanilamide, and naphthylethylenediamine
dihydrochloride were purchased from Sigma (St. Louis, MO). Asta Medica
(Frankfurt, Germany) provided the R-enantiomer of LA (R-LA), which is
the naturally occurring form, as kind gift. R-LA was dissolved in
dimethyl sulfoxide to obtain a stock concentration of 0.1 mol/l.
Anhydrous dextrose was obtained from Fisher Biotech (Fair Lawn, NJ).
NG-nitro-L-arginine
methyl ester hydrochloride
(L-NAME) was purchased from
Alexis (San Diego, CA). Dichlorodihydrofluorescein diacetate (DCFH-DA)
was from Molecular Probes, Eugene, OR.
2-[14C(U)]deoxy-D-glucose,
with a specific activity of 300-350 mCi/mmol, was purchased from
New England Nuclear Life Science Products (Boston, MA).
Methods
Experimental design. L6 myoblasts grown in 75-cm2 culture flasks were harvested and split to six wells of a six-well plate as described below. Thus cells in all six wells were derived from the same source. L6 myoblasts were then grown in six-well plates and differentiated to myotubes as described below. Myotubes prepared as such were used for all measurements reported in this study. Thus, for each experiment, data from control and treated cells were obtained from the same batch of myotubes prepared from the same stock of myoblasts under exactly similar conditions. For glucose uptake studies, two wells of each plate were utilized as control samples. Myotubes in one of these two wells were not treated with any agent to obtain basal glucose uptake values. Cells in the other control well were treated with cytochalasin B as described below to control for non-carrier-mediated transport of radiolabeled 2-[14C(U)]deoxy-D-glucose. Before glucose uptake studies were done, cells in the other four wells were either treated or not with agents described in the legends to Figs. 1-3.Cell
culture
and
differentiation. Differentiated
myotubes (30) obtained as described below were used in this study. For experiments, cells were seeded at a concentration of 0.03 × 106 cells per well in a six-well,
flat-bottom, tissue culture-treated polystyrene plate (Falcon, Becton
Dickinson Labware). In each well, cultures were grown in 3 ml of DMEM
supplemented with 10% FCS, 5 mM glutamine, 0.5%
D-glucose, 100 U/ml penicillin,
and 0.1 mg/ml streptomycin, in humidified air containing 5%
CO2 at 
37°C. On the
fifth day from the date of seeding, the culture medium was changed. The
new culture medium that was meant to stimulate cell differentiation was
serum deprived, containing 2% horse serum in place of 10% FCS. The
culture medium was changed again on
day 8 and day
11 after cell seeding. Glucose uptake
experiments were carried out either on
day
14 or
15 after cell seeding. Before each
experiment, formation of multinucleated myotubes and abundance were
verified by nuclear staining.
Cell
incubations
and glucose transport
assay. L6 myotubes were incubated with or without
TNF- (50 ng/ml), IFN- (500 ng/ml), and LPS (10 µg/ml) as
indicated in the legends to Figs. 1-3 for 24 h.
Treatment of myotubes with these inflammatory mediators did not
influence cell viability or membrane integrity as measured by lactate
dehydrogenase release from cells to the medium as well as standard
trypan blue exclusion assays (not shown). Where indicated, L-NAME (2 mM) or PDTC (0.2 mM)
was added 5 min or 2 h before cytokine or LPS treatment, respectively.
For the glucose transport assay, cells in each well were washed three
times with 1 ml of transport buffer (140 mM NaCl, 5 mM KCl, 2.5 mM
MgCl2, 1 mM
CaCl2, in 20 mM Tris-HEPES, pH
7.4). One milliliter of transport buffer was added to each well. In
experiments in which the effect of LA was studied, 2.5 µl of a 0.1 M
stock solution of LA in DMSO or a matched volume of DMSO was added to
each well for 30 min at 37°C before the start of glucose transport
assay. Transport assay was started by the addition of a mixture of
D-glucose (5 mM) and
2-[14C(U)]deoxy-D-glucose
(2 µCi/well) to each well and transferring the plate to an incubator
maintained at 37°C. Ten minutes after the start of glucose
transport assay, the six-well plate was placed on ice and 3 ml of
ice-cold transport buffer was added to each well to stop the transport
assay. After aspiration of the cold transport buffer, each well was
washed with 2 ml of ice-cold transport buffer three times. After this,
0.5 ml of 10% sodium dodecyl sulfate or 50 mM NaOH was added to each
well to disrupt and collect the cells. The cell lysate was collected in
a glass scintillation vial containing 5 ml of a scintillation cocktail
(Econo-Safe; Research Products International, Mount Prospect, IL).
After proper vortexing of the cell lysate and the scintillation
cocktail, each vial was subjected to
14C scintillation counting.
Glucose uptake values were normalized against total protein values
measured from lysates extracted in NaOH. The values were also corrected
for non-carrier-mediated transport by measuring glucose uptake in the
presence of 0.01 mM of cytochalasin B added just before the start of
the transport assay.
Cellular reduced glutathione measurement. Cells in monolayer were washed three times with DPBS and then treated with 0.5 ml of 4% monochloroacetic acid. The extract was mixed by resuspending and transferred to an Eppendorf tube that was snap frozen in liquid nitrogen. Before HPLC analysis, the extract was centrifuged (16,000 g, 5 min) and the supernatant filtered using 0.45-µM microfilterfuge tubes fitted with nylon membrane (Rainin, Woburn, MA). The sample pellet was dissolved in 1 N NaOH for determination of total protein using a BCA protein assay kit (Pierce, Rockford, IL).
Reduced glutathione (GSH) measurements were performed using a HPLC system coupled with a electrochemical coulometric detector (ESA, Chelmsford, MA). A C18 column (150 mm × 4.6 mm, 5-µm pore size; Alltech, Deerfield, IL) was used for GSH separation as described previously (20). GSH levels were expressed as nanomoles per milligram protein.
Nitrite and nitrate determinations. For the determination of nitrite and nitrate from cell culture medium, the medium was first deproteinized by adding 290 µl of 0.3 M NaOH to 400 µl of the culture medium as described previously (14). After incubation of the mixture for 5 min at room temperature, 290 µl of 5% (wt/vol) ZnSO4 was added. The mixture was then allowed to stand for another 5 min, after which it was centrifuged at 2,800 g for 20 min. The resulting supernatant was filtered through 0.45-µM microfilterfuge tubes fitted with a nylon membrane (Rainin). Nitrite and nitrate levels were detected from the deproteinized supernatant (100 µl) using an automated NOx analyzer (model TCI-NOX 1000; Tokyo Kasei Kogyo, Tokyo, Japan). This analyzer employs the technique of automated flow injection analysis (14). Nitrite reacts with Greiss reagent (1% wt/vol sulfanilamide and 0.1% wt/vol naphthylethylenediamine dihydrochloride in 2.5% wt/vol H3PO4) and forms a diazo compound. The absorbance of this compound is measured at 540 nm using a flow-through visible spectrophotometer (model S/3250; Soma Kogaku, Tokyo, Japan) connected to a chart recorder. Nitrate was determined by reducing it to nitrite using an A7200 copper-cadmium reduction column (Tokyo Kasei Kogyo) and then quantified as described above. Both sodium nitrite and nitrate solutions were used as standards. The volume of culture medium and total cellular protein in each well were not significantly different, allowing direct comparison of results obtained.
Determination of intracellular peroxides. Intracellular peroxides were detected using DCFH-DA as described previously (33). Myotubes were treated with the cytokines or LPS for 24 h as indicated in the legend to Fig. 5. After the treatment time, culture medium was aspirated from each well and the myotubes were washed once with DPBS at room temperature. A solution (1 ml) of DCFH-DA (50 µM) in DPBS was added to each well, and myotubes were incubated with the probe for 40 min at 37°C in dark. After the incubation, the DCFH-DA uptake and staining process was stopped by adding 3 ml of ice-cold DPBS to each well. After the entire overlay buffer was aspirated, 0.5 ml of fresh ice-cold DPBS was added to each well. Myotubes were detached from the monolayer using a disposable cell lifter (Fisher Scientific, Pittsburgh, PA). Dichlorofluorescein (DCF) fluorescence in cells was detected using a 488-nm argon ion laser for excitation in a flow cytometer (XL; Coulter, Miami, FL), and the 530 nm emission was recorded in fluorescence channel 1. Data were collected from at least 10,000 gated cells.
Statistical analyses. Differences between means of groups were determined by analysis of variance. The minimum level of significance was set at P < 0.05.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Glucose Uptake by L6 Myotubes
Compared with the basal rate in nontreated cells, treatment of L6 myotubes with IFN- or LPS significantly increased glucose uptake.
TNF- treatment did not influence glucose uptake in the myotubes,
however (Fig. 1). LA treatment of L6
myotubes also resulted in significant increase of glucose uptake
compared with the rate in nontreated control cells (Fig. 1). The
enhancing effects of IFN- and LPS on glucose uptake in L6 myotubes
was additive with the corresponding effect of LA. The stimulatory
effect of a combination of LPS or IFN- with LA on glucose uptake in
L6 myoblasts was markedly suppressed in cells that were pretreated with
the antioxidant PDTC (Fig. 1, A and
B). Under resting conditions, the
level of GSH in L6 myotubes was 94.17 ± 7.4 nmol/mg protein.
Inhibition of intracellular GSH synthesis by treatment of cells with
BSO for 48 h decreased cellular GSH content to 17.82 ± 2.92 nmol/mg protein. In GSH-depleted cells, the stimulatory effects of both IFN-
and LPS on glucose uptake by L6 myotubes were significantly higher
(Fig. 2). TNF- alone did not influence
glucose uptake even in GSH-depleted cells (not shown). In combination,
TNF-, IFN-, and LPS significantly increased glucose uptake in L6
myotubes compared with the corresponding basal rate. Treatment of
myotubes with L-NAME, a NO
synthase inhibitor, did not influence the glucose uptake stimulatory
effect of the cytokine and LPS combination (Fig.
3). The enhancing effect of a combination
of TNF-, IFN-, and LPS on glucose uptake in L6 myotubes was
additive with the corresponding effect of LA. The effect of a
combination of TNF-, IFN-, LPS, and LA on L6 myotube glucose
uptake was not influenced by
L-NAME treatment (Fig. 3).
Results are presented as means ± SD of at least three separate
experiments.
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Inducible NO Generation
As evidence for the generation of NO production, nitrite and nitrate content of the cell culture medium were determined. When L6 myotubes were treated with any one of TNF-, IFN-, or LPS, NO production by
cells was not increased. When used in combination, however, TNF-,
IFN-, and LPS treatment resulted in a marked increase in nitrite and
nitrate content in the cell culture medium (Fig.
4A).
Pretreatment of the myotubes with
L-NAME, but not
D-NAME (not shown), completely
abolished the induced generation of NO in response to a combination of
TNF-, IFN-, and LPS treatment (Fig.
4B).
L-NAME treatment alone slightly
increased basal production of nitrate and nitrite by L6 myotubes. This
observation is consistent with previous data showing that
L-NAME treatment alone resulted in an 80% increase in basal nitrite production in L6 myotubes (1).
Results are presented as means ± SD of at least three separate
experiments.
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Intracellular Peroxides and GSH
Treatment of L6 myotubes with IFN- or LPS increased the level of
intracellular peroxides as estimated by the development of DCF
fluorescence. TNF- treatment did not influence intracellular peroxide level, however. A combination of TNF-, IFN-, and LPS also increased the level of intracellular peroxides and decreased the
level of intracellular GSH compared with the corresponding levels in
nontreated cells (Fig. 5). Results are
presented as means ± SD of at least three separate experiments.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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This study shows that in skeletal muscle cells, cytokine-induced
upregulation of glucose uptake is mediated by a redox-dependent mechanism. In support of this, it has been shown that such effect of
LPS and IFN- individually, and of a combination of LPS, IFN-, and
TNF-, is 1) inhibited by
treatment of cells with the antioxidant PDTC and
2) potentiated in GSH-deficient
cells with impaired antioxidant defenses. Also, the stimulatory effect
of LPS and IFN- individually, and of a combination of LPS, IFN-,
and TNF-, on glucose uptake in L6 myotubes was associated with
increased accumulation of intracellular peroxides and loss of
intracellular GSH. A recent study concluded that a combination of LPS,
IFN-, and TNF- upregulates glucose uptake in L6 myotubes by an
NO-dependent mechanism (1). The individual effects of LPS, IFN-, and
TNF- on glucose uptake by L6 myotubes and cellular NO production
were not reported (1). In the present study, results obtained from
experiments studying the individual effects of LPS, IFN-, and
TNF- as well as a combination of the three activators provide
evidence against a role of NO in mediating the stimulatory effect of
the above-mentioned agents on glucose uptake in L6 myotubes.
Redox-dependent mechanisms have been shown to regulate a wide variety
of cellular function and response (35, 37). Our current observation
that cytokine-induced glucose uptake by L6 myotubes is redox regulated
and perhaps reactive oxygen species mediated is consistent with a
previous report showing that oxidants may indeed stimulate skeletal
muscle glucose uptake via increased expression of GLUT-1 mRNA and
protein (23, 24). Exposure of L6 myotubes to prolonged low-grade
oxidative stress results in increased GLUT-1 expression at both the
protein and mRNA levels, leading to elevated glucose transport
activity. Oxidative stress increased GLUT-1 transcription rate by
activating activator protein 1 binding to enhancer 1 of the GLUT-1
gene. (24). Inhibition of intracellular GSH synthesis impairs the
antioxidant defense system, resulting in increased accumulation of
intracellular peroxides (15, 27). Previously we have shown that in L6
cells, BSO treatment markedly depletes cellular GSH and potentiates
TNF--induced activation of the peroxide-inducible transcription
factor nuclear factor 
B (36). The stimulatory effect of IFN- or
LPS on glucose uptake was potentiated in GSH-deficient cells,
suggesting that the infection-related agonists may have functioned via
an oxidant-dependent mechanism. Indeed, treatment of L6 cells with
IFN- or LPS increased the level of intracellular peroxides as
detected by DCF fluorescence. Moreover, treatment of cells with the
antioxidant PDTC inhibited LPS- or IFN--induced glucose uptake. PDTC
is a reducing agent that, when treated at a concentration and duration
as was used in this study, has been shown to enhance antioxidant
defenses in L6 cells (36). All of these findings support the conclusion that both LPS and IFN- increase glucose uptake in L6 myotubes by a
reactive oxygen species-dependent mechanism. In L6 myotubes, TNF-
treatment alone did not influence the level of intracellular peroxides
as well as the rate of glucose uptake. In combination, LPS, IFN-,
and TNF- markedly enhanced glucose uptake in L6 myotubes. This
effect was accompanied with oxidative stress, as indicated by increased
level of intracellular peroxide and loss of intracellular GSH. The
ability of cytokines and endotoxins to induce oxidative stress has been
previously demonstrated (11, 17, 32, 43).
Recently it has been reported that in L6 myotubes a combination of LPS,
IFN-, and TNF- markedly enhances NO production by inducing the
activity of inducible NO synthase (1). The same treatment also
increased glucose uptake in those cells. On the basis of a set of
experiments studying the combined effect of LPS, IFN-, and TNF-
on glucose uptake but not that of the individual cell activating
agents, it was concluded that LPS, IFN-, and TNF- enhance glucose
uptake by an NO-dependent mechanism (1). Our observations from the
additional study of the individual effects of LPS, IFN-, and TNF-
provide evidence against a role of NO. Consistent with previous reports
(1), we have observed that neither LPS, IFN-, nor TNF- is able
individually to induce NO synthesis in L6 myotubes. Despite this, both
LPS and IFN- are able to stimulate glucose uptake in these cells.
When treated to cells in combination, LPS, IFN-, and TNF-
markedly enhanced NO production as well as glucose uptake in L6
myotubes. However, this effect of a combination of LPS, IFN-, and
TNF- on skeletal muscle glucose uptake was not influenced by
inhibition of inducible NO synthase activity. This line of evidence
further confirms our contention that NO is not involved in mediating
the effect of a combination of LPS, IFN-, and TNF- on skeletal
muscle glucose uptake. L-NAME is
a commonly used inhibitor of inducible NO synthase activity. That this
inhibitor was potent is clearly evident from our results showing that
increased NO production in response to treatment of a combination LPS,
IFN-, and TNF- was completely abrogated in
L-NAME-treated cells.
The development of malnutrition is often rapid in critically ill
patients with sepsis and severe trauma. Hypermetabolism, associated
with protein and fat catabolism, negative nitrogen balance,
hyperglycemia, and resistance to insulin, constitutes the hallmark of
this response (4). A common property of LPS, IFN-, and TNF- is
that individually each of these three agents may cause insulin
resistance. TNF- is overexpressed in the adipose tissue of obese
rodents and humans and is associated with insulin resistance (34).
Insulin resistance caused by TNF- has been thought to be implicated
in disorders such as obesity and non-insulin-dependent diabetes
mellitus (28, 41). Consistent with this, neutralization of TNF- in
obese
fa/fa
rats was observed to cause a significant increase in the peripheral
uptake of glucose in response to insulin. (18). Many viral infections
cause insulin resistance by inducing IFN production (19, 22). In
skeletal muscle tissue, endotoxin shock is known to cause insulin
resistance (31). In L6 myotubes, LA treatment has been shown to be
associated with an intracellular redistribution of GLUT-1 and GLUT-4
glucose transporters, similar to that caused by insulin, with minimal
effects on GLUT-3 transporters. On the basis of these observations, it
has been proposed that elements of the insulin-signaling pathway
mediate the effect of LA on glucose uptake (10). In a more recent
study, however, it was determined that although a portion of LA action
on glucose transport in mammalian skeletal muscle is mediated via the
insulin signal transduction pathway, a majority of the direct effect of LA on skeletal muscle glucose transport is insulin independent (16).
Results of the current study agree with this contention because,
although a combination of LPS, IFN-, and TNF- causes decreased
insulin sensitivity (1), such treatment is not able to influence the
ability of LA to stimulate glucose uptake in skeletal muscle cells.
These observations lead to the hypothesis that under conditions of
acute infection that is accompanied with insulin resistance, LA may
have therapeutic implications in restoring glucose availability in
tissues such as the skeletal muscle.
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ACKNOWLEDGEMENTS |
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This work was supported by National Institutes of Health Grants GM-27345 and DK-50430, the Finnish Ministry of Education, and the Juho Vainio Foundation of Helsinki, Finland.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: C. K. Sen, Life Sciences Addition, Bldg. 20A, Rm. 251 C, Mail Stop 3200, Lawrence Berkeley National Laboratory/EETD, Univ. of California, Berkeley, CA 94720 (E-mail: cksen{at}socrates.berkeley.edu).
Received 17 September 1998; accepted in final form 2 February 1999.
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
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P < 0.05, significantly
higher than R-LA- or IFN-
P < 0.05, significantly
lower than all other bars in panel.
