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on Glucose Metabolism in Cultured Human Muscle Cells from Nondiabetic and Type 2 Diabetic Subjects1
Veterans Affairs Medical Center and Department of Medicine (0673), University of California-San Diego (T.P.G., L.C., S.M., R.R.H.), La Jolla, California 92093; and the Veterans Affairs Medical Center and Department of Medicine, University of Arkansas for Medical Sciences (P.A.K.), Little Rock, Arkansas 72205
Address all correspondence and requests for reprints to: Dr. Theodore P. Ciaraldi, Department of Medicine (0673), University of California-San Diego, La Jolla, California 92093. E-mail: tciaraldi{at}ucsd.edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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(TNF) on glucose uptake and
glycogen synthase (GS) activity were studied in human skeletal muscle
cell cultures from nondiabetic and type 2 diabetic subjects. In
nondiabetic muscle cells, acute (90-min) exposure to TNF (5 ng/ml)
stimulated glucose uptake (73 ± 14% increase) to a greater
extent than insulin (37 ± 4%; P < 0.02).
The acute uptake response to TNF in diabetic cells (51 ± 6%
increase) was also greater than that to insulin (31 ± 3%;
P < 0.05). Prolonged (24-h) exposure of
nondiabetic muscle cells to TNF resulted in a further stimulation of
uptake (152 ± 31%; P < 0.05), whereas the
increase in cells from type 2 diabetics was not significant compared
with that in cells receiving acute treatment. After TNF treatment,
the level of glucose transporter-1 protein was elevated in nondiabetic
(4.6-fold increase) and type 2 (1.7-fold) cells. Acute TNF treatment
had no effect on the fractional velocity of GS in either nondiabetic or
type 2 cells. Prolonged exposure reduced the GS fractional velocity in
both nondiabetic and diabetic cells. In summary, both acute and
prolonged treatment with TNF up-regulate glucose uptake activity in
cultured human muscle cells, but reduce GS activity. Increased skeletal
muscle glucose uptake in conditions of TNF excess may serve as a
compensatory mechanism in the insulin resistance of type 2 diabetes. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(TNF). Expression of TNF is increased in
adipose tissue and muscle, the major insulin target tissues, of
insulin-resistant humans (1, 2, 3) and animals (4), suggesting that
elevated TNF is a causative or contributory factor in the
development of insulin resistance, especially in obesity and diabetes
(reviewed in Ref. 5). Infusion of animals and humans with TNF can
lead to whole body insulin resistance, localized to both the liver and
peripheral tissues, especially muscle (6, 7, 8). Meanwhile, infusion of
insulin-resistant animals with a soluble TNF-binding protein
improved insulin action in vivo (5).
At the cell level, extensive investigation has occurred in adipocytes,
where TNF treatment results in insulin resistance for stimulation of
glucose transport (9, 10). Several potential mechanisms for
TNF-induced insulin resistance have been suggested, including
down-regulation of the glucose transporter-4 (GLUT4) glucose
transporter (10) and impaired insulin signaling (11, 12). However, it
is muscle that represents the major site of glucose disposal,
especially in response to insulin, and this tissue has not been studied
in the same depth. Elevation of TNF levels can lead to insulin
resistance for both glucose disposal into muscle (6, 7) and suppression
of hepatic glucose output (6, 7). Paradoxically, in the fasting (basal)
state, hypoglycemia can occur, and glucose uptake into muscle is
increased after TNF treatment (6, 7, 13).
TNF is a potent lipolytic agent in adipose tissue (9), leading to
the possibility that both TNF and FFA released from adipose tissue
could be acting as paracrine factors influencing metabolism and insulin
action in adjacent skeletal muscle. As FFA can inhibit insulin
stimulation of glucose transport in both fat (14) and muscle (15, 16),
it is possible that the effects of TNF on muscle might be indirect
in nature. To investigate the direct effects of TNF on skeletal
muscle glucose metabolism, we used the human skeletal muscle culture
system. These cells express the morphological, biochemical, and
metabolic properties of differentiated muscle, including insulin
responsiveness (17). Most importantly, cells obtained from type 2
diabetic subjects display defects in glucose transport (18) and
glycogen synthase (GS) (19) that reflect the impaired function observed
in vivo and in muscle biopsies. In this way we could
determine whether there were any differences between normal and
diabetic muscle with regard to the influence of TNF.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-actin was obtained from Sigma Chemical Co., Inc. (St.
Louis, MO). Antirabbit and antimouse IgGs conjugated with horseradish
peroxidase and the enhanced chemiluminesence kit were obtained from
Amersham (Arlington Heights, IL). Protein assay kits and
electrophoresis chemicals were purchased from Bio-Rad Laboratories, Inc. (Hercules, CA). Pepstatin, leupeptin,
phenylmethylsulfonylfluoride, 2-deoxyglucose, L-glucose,
glycogen, TNF, and other reagents were purchased from Sigma Chemical Co.
Human subjects
Nondiabetic and type 2 diabetic subjects were recruited for
muscle biopsy. Glucose tolerance was determined from a 75-g oral
glucose tolerance test (20). Insulin action was analyzed by a 3-h
hyperinsulinemic (300 mU/m2·min) euglycemic
(5.0–5.5 mM) clamp; the glucose disposal rate was
determined during the last 30 min of the clamp (21). Subject
characteristics are summarized in Table 1
. The diabetic group was significantly
older and more obese than the nondiabetics. Impairments of the
maximally insulin-stimulated glucose disposal rate confirmed the
insulin resistance of the diabetic group (Table 1). The experimental
protocol was approved by the committee on human investigation of the
University of California-San Diego (La Jolla, CA). Informed written
consent was obtained from all subjects after explanation of the
protocol. Biopsy of the vastus lateralis muscle was performed according
to previously described procedures (21).
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MEM containing 2% FBS, 1% fungibact,
100 U/ml penicillin, and 100 µg/ml streptomycin. Fusion medium was
changed every 2 days to reduce glucose depletion. All studies were
carried out on first passage cultures. The extent of differentiation
was established by fluorescent microscopic observation of
multinucleation and striation patterns of skeletal myosin fast (heavy
chain) and induction of -sarcomeric actin protein as described in
previous reports (17). When indicated, TNF was added to the medium
24 h before acute hormone exposure. TNF treatment had no effect
on these markers of muscle differentiation.
Glucose uptake assay
The procedure for glucose uptake measurement has been described
previously (18). Medium was added to the cells together with insulin (0
or 33 nM) and/or TNF (0–5 ng/ml), and the cells were
incubated for 90 min in a 5% CO2 incubator before washing
and transport assay. An aliquot of the suspension was removed for
protein analysis using the Bradford method (22). The uptake of
L-glucose was used to correct each sample for the
contribution of diffusion.
Membrane preparation
Cells for membrane preparation were grown in 100-mm dishes and
treated as described for activity assays. Total membranes were prepared
as described previously (18). Cells were scrapped from dishes,
collected by centrifugation, and homogenized with a Dounce homogenizer
(Kontes Co., Vineland, NJ). After centrifugation at 750 x
g for 3 min, the pellet was rehomogenized and recentrifuged,
and the supernatants were combined. Centrifugation of the supernatant
at 190,000 x g for 60 min produced a total membrane
pellet. The membranes were resuspended in homogenization buffer, and
the protein content was determined.
Detection of glucose transporter proteins
Membrane preparations were diluted 1:1 in 2 x Lamelli’s
buffer without ß-mercaptoethanol (23) and heated for 5 min at 90 C.
Proteins were separated on 10% SDS-PAGE gels and then transferred to
nitrocellulose (24). GLUT1 was identified using a rabbit polyclonal
antiserum against the rat brain glucose transporter (RaGLUTRANS,
East Acres Biologicals). A polyclonal antiserum specific
for GLUT4 (RaIRGT) was also employed. The second antibody was
antirabbit IgG conjugated with horseradish peroxidase. Immune complexes
were detected using an enhanced chemiluminescence kit. Quantitation was
performed with a scanning laser densitometer (ScanAnalysis,
Biosoft, Ferguson, MO).
GS activity
GS activity was measured as described in detail previously (19).
GS activity was assayed at a physiological concentration of substrate
(0.3 mM UDP-[14C]glucose) in parallel
incubations with 0.1 and 10 mM glucose-6-phosphate. GS
activity is expressed as nanomoles of UDP-[14C]glucose
incorporated into glycogen per min/mg total protein or as fractional
velocity (FV), a percentage of the ratio of activity at 0.1
mM glucose-6-phosphate/10 mM
glucose-6-phosphate.
Glycogen synthesis
Glycogen synthesis was determined in differentiated myotubes as
[14C]D-glucose incorporation into glycogen
during a 1-h incubation at 37 C (25). Treated cells were washed free of
TNF before incubation with or without insulin (33 nM).
After incubation, cells were rinsed four times with PBS at 4 C
and solubilized with 1 N NaOH at 55 C for 1 h. An
aliquot (100 µl) of the lysate was removed for protein analysis.
Lysates were neutralized with 10 N HCl, boiled for 30 min,
and then cooled on ice. Glycogen was precipitated with 95% ethanol,
and the pellet was washed by resuspension and precipitation. The final
glycogen pellets were resuspended in 0.5 ml H2O and mixed
with scintillation fluid, and radioactivity was determined by liquid
scintillation counting. Results are expressed as nanomoles of glucose
converted to glycogen per h/mg protein.
Immunoblotting
Western blot analysis was performed by the method detailed
previously (19). GS was identified using an affinity-purified
polyclonal antibody raised in rabbits against an oligopeptide (12-mer)
specific for the carboxyl-terminal sequence of GS (a gift from Dr. L.
Groop, Malmo, Sweden). The secondary antibody was antirabbit IgG
conjugated with horseradish peroxidase. Sarcomeric -action was
detected with a monoclonal antibody and antimouse IgG conjugated to
horseradish peroxidase. Proteins were visualized with the enhanced
chemiluminescence Western blot detection kit (Amersham)
and exposed to autoradiograph film (XAR-5, Eastman Kodak Co., Rochester, NY). The intensity of the bands was quantified
by scanning laser densitometry.
Statistical analysis
Statistical significance was evaluated using Student’s
t test and two-tailed P values were calculated.
Paired analysis was performed for comparisons of insulin action and
acute and prolonged TNF exposures in the same sets of cells. Results
presented as the percent change were obtained from comparisons with
paired controls. Significance was accepted at P <
0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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on glucose uptake infusion has been shown to have rapid
effects on insulin-stimulated glucose disposal (7, 13). The acute
effects of TNF on glucose uptake in cultured muscle cells were
tested by treating cells for 90 min in the absence or presence of
insulin (33 nM), conditions shown to reveal maximal insulin
stimulation of uptake (18). In cells from nondiabetic subjects, insulin
treatment caused an approximately 50% increase over basal activity
(paired comparison, P < 0.05). TNF treatment led to
a dose-dependent increase in uptake activity (not shown). Stimulation
due to a maximal dose of TNF (5 ng/ml; 75 ± 14%) was greater
than that due to insulin (Fig. 1;
P < 0.02). The combination of insulin and TNF
(77 ± 16% increase) did not cause any greater stimulation than
that seen with TNF alone.
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). However, similar results for the effects of TNF
were observed for glucose uptake in muscle cells from type 2 diabetic
subjects. The stimulation resulting from insulin treatment (31 ±
4%) was less than that observed after TNF exposure (51 ± 6%;
P < 0.05). There was no additive or synergistic effect
of combining insulin and TNF (72 ± 18% increase;
P = NS compared with TNF alone).
Many effects of TNF to cause insulin resistance in cultured cells
require more prolonged exposure to the cytokine (5). To investigate the
influence of extended TNF exposure on muscle cell glucose uptake,
cells were treated for 24 h with a maximal dose (5 ng/ml). The
cells were then washed free of TNF before the acute insulin
treatment. Control cells retained insulin responsiveness (Fig. 1). In
nondiabetic cells, prolonged TNF treatment stimulated uptake
activity to 152 ± 31% over basal, a greater extent than after
acute treatment (74%; P < 0.05). There was a small
additional effect of acute insulin stimulation in TNF-treated cells
(173 ± 35% stimulation; P < 0.05 compared with
chronic TNF alone). Prolonged TNF treatment also elevated uptake
in diabetic cells (76 ± 10%). However, unlike the case in
nondiabetic cells, there was no further significant increase over that
due to acute exposure (51%). Acute insulin exposure of chronically
TNF-treated diabetic cells resulted in a small further stimulation
to 100 ± 13% of the basal level (P < 0.05
compared with chronic TNF alone).
Regulation of glucose transporter expression
One possible mechanism by which TNF could modulate glucose
transport activity would be through control of glucose transporter
protein levels. Total membranes were prepared from muscle cells treated
for 24 h in the absence or presence of 5 ng/ml TNF. Transporter
protein expression was determined by Western blotting. A representative
autoradiogram for GLUT4 along with quantitation of such measurements
performed on a larger set of cells are presented in Fig. 2A. GLUT4 protein levels were similar in
nondiabetic and diabetic cells, confirming our previous results (17)
and in agreement with findings in muscle biopsies (26). Prolonged
TNF treatment had no effect on GLUT4 protein expression in either
nondiabetic or diabetic cells. Such a result might explain the lack of
any increase in insulin stimulation of transport over the TNF
effect.
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treatment (Fig. 2B). The effect of chronic TNF
treatment on GLUT1 expression (1.7 ± 0.2-fold increase;
P < 0.05) was much less in type 2 diabetic cells,
consistent with the lesser up-regulation of transport activity (Fig. 1). It should be noted that only total membrane transporter content was
measured in these studies; any potential additional effects of TNF
on transporter localization, such as translocation to the plasma
membrane, would not be apparent from this analysis.
Influence of TNF on GS and glycogen production
A major fate of glucose, once transported into skeletal muscle, is
storage as glycogen. The activity of the rate- limiting enzyme for
this process, GS, was monitored after acute treatment with insulin (33
nM) and/or TNF. Insulin stimulated the FV of synthase by
57 ± 14% (P < 0.05) in nondiabetic cells.
TNF, when added to cells for 90 min, had no significant effect on
synthase activity in either the absence or presence of insulin (Fig. 3); insulin responsiveness was retained
in the presence of TNF. Although both basal and insulin-stimulated
synthase FVs were lower in diabetic muscle cells than in those of
nondiabetics (P < 0.05; Fig. 3), similar behavior was
observed in diabetic cells; the insulin response (70 ± 19%
stimulation) was not altered by TNF treatment (61 ± 18%
stimulation). Basal synthase activity in diabetic cells was also not
influenced by acute exposure to TNF.
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reduced the GS FV (Fig. 3). In
nondiabetic cells a similar relative decrease was seen for both basal
(to 64 ± 11% of control; P < 0.05) and
insulin-stimulated (71 ± 10% of control) activities. Insulin
responsiveness was retained after TNF treatment. Diabetic muscle
cells displayed a smaller response to prolonged TNF exposure; basal
activity was 83 ± 11% of the control value (P <
0.05), and insulin-stimulated activity was reduced to 77 ± 7% of
the control value. Again, synthase remained responsive to insulin.
These reductions in synthase activity occurred with no change in either
total enzyme activity or enzyme protein expression (Table 2) and most likely represent alterations
in the activation state of the enzyme.
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on glucose transport
(positive) and of GS (none or negative) on the portion of glucose
metabolism in muscle cells represented by storage in glycogen was
investigated in several ways. With regard to the total glycogen content
of nondiabetic cells, neither acute nor prolonged TNF treatment had
any effect on glycogen stores (Table 3).
The glycogen content of control diabetic cultures was lower than that
in nondiabetics (P < 0.01), but again TNF had no
effect after either acute or prolonged exposure.
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treatment (Fig. 4). Insulin
responsiveness was also retained. The large increases in transport
activity seen under the same conditions did not direct more glucose
toward glycogen. The same result was obtained in diabetic muscle cells
(Fig. 4); both basal and insulin-stimulated glycogen synthesis were
unaltered after TNF treatment.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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is primarily secreted from macrophages and has a
major role in mediating inflammatory responses (27), it is also
produced in muscle (3) and adipose tissue (1) and can influence glucose
and lipid metabolism (28). Recently, several lines of evidence have
been advanced that support the hypothesis that TNF is involved in
the development of insulin resistance in obesity and type 2 diabetes
(2, 5). Expression of TNF is elevated in obese and diabetic humans
(2, 3) as well as in animal models of obesity-linked insulin resistance
(4). TNF expression is also elevated in adipose tissue (1) and
muscle (3) of insulin-resistant humans, is correlated with obesity, and
is reduced with weight loss (2). There are also numerous reports that
TNF treatment of rats (6, 7) or dogs (13) led to insulin resistance
for both peripheral glucose disposal, mainly into muscle, and
suppression of hepatic glucose output. Neutralization of TNF by
infusion of a soluble TNF-binding protein ameliorated insulin
resistance in fa/fa rats (5).
Mechanisms by which TNF might cause insulin resistance have been
elucidated by studies in cultured cells. In 3T3-L1 adipocytes,
incubation with TNF resulted in down-regulation of GLUT4 (10, 29).
Impairments of insulin signaling were observed as reductions in insulin
effects on receptor autophosphorylation and insulin receptor
substrate-1 phosphorylation (11). These effects occurred together with
increased serine phosphorylation of insulin receptor substrate-1 (11).
Complicating factors in evaluating the effects of TNF on adipocytes
include evidence that the cytokine is a potent lipolytic agent (9) and
also causes adipocyte dedifferentiation (10, 29).
The literature concerning the effects of TNF on glucose metabolism
and insulin action in skeletal muscle is more mixed. Although there is
a report in L6 myocytes that TNF treatment reduced glucose transport
and glycogen synthesis, possibly through impairment of protein
phosphatase-1 (30), other investigators have found no effect in the
same cell line (31). Incubation of isolated soleus muscles with TNF
also failed to have any effect on glucose uptake (32). Multiple
investigators have found that infusion of TNF, although generating
insulin resistance (6, 7, 8, 13), also elevated basal glucose disposal and
uptake into muscle and adipocytes (33, 34).
Stimulatory effects of acute TNF treatment on glucose metabolism
in vivo (13) are similar to our finding of the ability of
TNF to rapidly stimulate glucose uptake in human skeletal muscle
cells (Fig. 1), although the greater potency than insulin was an
unexpected finding. The lack of additivity of insulin and TNF after
acute exposure suggests either that both agents work through the same
pathways or that TNF stimulates transport to the maximal capacity of
the system. However, the failure of TNF to cause significant
stimulation of GS (Fig. 4) suggests that TNF replicates only some of
the actions of insulin. TNF might be acting at a point where
signaling to transport diverges from that for GS activation.
Although the mechanism for the acute transport stimulatory effect of
TNF is unknown, the major cause of the chronic increase in transport
activity seems clear; up-regulation of the GLUT1 protein (Fig. 2).
Up-regulation of GLUT1 has also been seen in human adipocytes cultured
with TNF (9). In addition, a recent report in L6 cells found that
24-h TNF treatment in combination with interferon-
up-regulated
basal glucose transport and GLUT1 protein expression (35); these
changes were linked to the induction of inducible nitric oxide synthase
(NOS) and nitric oxide production. In 3T3 fibroblasts, TNF has been
shown to cause GLUT1 messenger RNA stabilization through synthesis of a
factor that binds to the 3'-UTR (untranslated region) of the
gene (36); either or both of these mechanisms may be active in skeletal
muscle. Diabetic muscle cells showed smaller changes in both transport
activity and GLUT1 protein in response to TNF. This difference may
be indicative of partial TNF resistance, at least for one response,
in diabetic muscle. This would be in addition to the impairments of
glucose transport activity preserved in cultured human muscle cells. If
inducible NOS is involved in mediating the GLUT1 response to chronic
TNF exposure (35), then the reduced response in diabetic cultured
muscle cells may indicate an impairment in the NOS system in
diabetes.
The response of GLUT4 to TNF appears to be tissue specific. GLUT4
protein levels in muscle are unaltered in animals with elevated TNF
levels (37, 38), similar to our finding. Meanwhile, decreases are
common in TNF-treated adipocytes (10, 29, 29). Although
dedifferentiation of adipocytes in response to TNF could account for
some loss of GLUT4, this would not occur in terminally differentiated
primary adipocytes; some adipocyte-specific factor might be involved in
the differential response.
Beyond effects on final metabolic responses, TNF has also been shown
to generate insulin resistance both in vivo (6, 7) and in
cell systems (9, 10, 11, 12). Due to the TNF-induced elevations in basal
glucose uptake, it is difficult to draw any conclusions about the
effect of TNF on insulin action for this response. Is there little
or no further insulin stimulation because the cells are now insulin
resistant or because the maximal capacity of the system has been
attained? Yet GS and glucose incorporation into glycogen remain
normally insulin responsive after TNF treatment, suggesting that
under these experimental conditions, TNF alone is not causing
insulin resistance.
The additional glucose entering muscle cells after either acute or
prolonged TNF treatment was not directed toward storage in glycogen,
as seen by the lack of change in glycogen content or net glycogen
synthesis. A similar lack of change in glycogen content was seen in
isolated soleus strips after incubation with TNF (32). Elevations of
basal glucose uptake and GLUT1 protein, seen in L6 cells after cytokine
treatment (35) and presumably linked to elevations in TNF, were
accompanied by increases in lactate release, suggesting that the
additional glucose might be directed toward glycolysis and away from
glycogen synthesis. The slight reduction in GS activity could also
contribute to glycolysis being preferred over storage in glycogen. This
scenario is conjecture, as glycolytic intermediates were not measured
in our studies.
As both basal and insulin-stimulated GS FVs are reduced, even as total
activity and enzyme protein expression are unaltered, it is the
activation state of the enzyme that must be influenced by TNF.
Insulin regulates synthase activity by dephosphorylation of the enzyme.
However, this is a rapid response and occurs within the time frame
where there was no acute effect of TNF on synthase activity. The
more delayed effect of TNF to reduce synthase activity could be due
to the accumulation of an intracellular intermediate that would exert
allosteric effects on the synthase enzyme. Conversely, TNF could
gradually alter the expression and activity of phosphatases or kinases
that activate or deactivate the enzyme, respectively.
The opposing effects of TNF on metabolism in adipose tissue and
skeletal muscle may serve several roles. One would be to divert
substrates from adipose tissue, by lipolysis or inhibition of glucose
transport, to meet the energy needs of muscle. This would preserve
substrate stores within the muscle at the expense of adipose tissue.
TNF stimulation of muscle glucose transport, which would be greater
in the presence of the higher cytokine levels characteristic of
insulin-resistant states, could also partially compensate for impaired
glucose transport and insulin resistance due to either elevated FFA
levels or the defects intrinsic to skeletal muscle in type 2 diabetes.
The elevated glucose and insulin levels present in diabetes and other
insulin-resistant states could also influence the final effect of
TNF; the current studies investigated direct effects of TNF under
normal glycemic, insulinemic, and triglyceridemic conditions and might
not be fully reflective of the more complicated situation present in
type 2 diabetes. In addition, resistance to the chronic ability of
TNF to up-regulate glucose transport and GLUT1 expression would
represent an additional impairment in type 2 diabetic skeletal muscle
and limit whatever effects TNF might have to compensate for impaired
glucose uptake in diabetes.
There is compelling evidence that TNF can lead to skeletal muscle
insulin resistance in the in vivo, whole body context. What
the current results, obtained in an isolated muscle cell culture
system, suggest is that this response may be an indirect one. Although
TNF may act directly on skeletal muscle to increase glucose uptake
and promote glucose utilization, possibly toward oxidation, the
cytokine would also be activating lipolysis in adipose tissue. The
resulting elevated FFA levels could contribute to insulin resistance in
the adjacent muscle. This supposition is supported by the finding that
antidiabetic thiazolidinediones, which lower FFA levels (39), can
improve TNF-induced insulin resistance both in vivo (8)
and in adipocytes (10, 40). More direct evidence comes from a report
that thiazolidinedione treatment of 3T3-L1 adipocytes can block the
lipolytic effects of TNF (41). However, the hypothesis that elevated
FFA levels may be causing insulin resistance also needs to be tested
directly in cultured human muscle cells. The smaller changes in
diabetic muscle cells in glucose transport and GLUT1 up-regulation to
TNF suggest that in addition to insulin resistance, type 2 diabetics
may have an impaired response to this potential compensatory effect of
TNF.
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Footnotes |
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Received July 1, 1998.
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, P < 0.05 vs.
insulin-treated control; §, P < 0.05
vs. paired basal values; 
, P <
0.05 vs. 90-min TNF treatment.
