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Original Articles |
B and Stimulates IB in Mononuclear Cells in Obese Subjects: Evidence for an Anti-inflammatory Effect?
Division of Endocrinology, Diabetes & Metabolism, State University of New York at Buffalo and Kaleida Health, Buffalo, New York 14209
Address all correspondence and requests for reprints to: Paresh Dandona, M.D., Director, Diabetes-Endocrinology Center of WNY, 3 Gates Circle, Buffalo, New York 14209. E-mail: pdandona{at}kaleidahealth.org
Abstract
In view of the fact that insulin resistance is associated with
atherogenesis and that troglitazone, an insulin
sensitizer, has anti-inflammatory effects, which may be potentially
antiatherogenic in the long term, we have now investigated whether
insulin has potential anti-inflammatory effects. We infused 2.0 to 2.5
IU/h in 5% dextrose (100 mL/h) iv into 10 obese subjects for 4 h
followed by 5% dextrose alone for 2 h. The rate of insulin
infusion was varied to maintain glucose concentrations as close to the
baseline as possible. Blood samples were obtained before and at 2, 4,
and 6 h. Subjects were also infused with 5% dextrose without
insulin and with saline on separate occasions. Intranuclear nuclear
factor 
B (NFB) in mononuclear cells fell at 2 and further at
4 h, reverting toward the baseline at 6 h
(P < 0.05). IB increased significantly at
2 h, increasing further at 4 h and remaining elevated at
6 h (P < 0.001). Reactive oxygen species
(ROS) generation by mononuclear cells fell significantly at
2 h and fell further at 4 h; it partially reverted to
baseline at 6 h (P < 0.005).
p47phox subunit, the key protein of nicotinamide adenine
dinucleotide phosphate oxidase also fell at 2 h and 4 h,
reverting toward the baseline at 6 h (P <
0.05). In addition, soluble intercellular adhesion molecule-1
(sICAM-1), monocyte chemoattractant protein-1 (MCP-1), and plasminogen
activator inhibitor-1 (PAI-1) fell significantly following
insulin infusion. Glucose or saline infusions without insulin caused no
alteration in NFB, IB, ROS generation, p47phox
subunit, sICAM-1, MCP-1, or PAI-1.
We conclude that insulin has a potent acute anti-inflammatory effect
including a reduction in intranuclear NFB, an increase in IB, and
decreases in ROS generation, p47phox subunit, plasma
soluble intercellular adhesion molecule-1 (sICAM-1), monocyte
chemoattractant protein-1 (MCP-1), and plasminogen activator
inhibitor-1 (PAI-1. This acute anti-inflammatory effect, if
demonstrated in the long term, may have implications for
atherosclerosis and its complications.
MONONUCLEAR CELLS (MNC), monocytes in particular, are cellular mediators of inflammation (1, 2). The monocyte is also the cell that initiates the process of atherosclerosis when it gets attached to abnormal/damaged endothelium (3, 4). Monocytes and MNC are known to be active in atherosclerosis and diabetes mellitus. Increased reactive oxygen species (ROS) generation by MNC and monocytes leads to increased tissue/cellular damage (5, 6), increased lipid peroxidation (7), protein oxidation (8), and DNA damage (9) in diabetic patients. Increased lipid peroxidation and increased activation of monocytes are key processes in the formation of foam cells and the pathogenesis of the fatty streak, atherosclerosis (10, 11). Atherosclerosis is now thought to be an inflammation of the arterial wall (1).
The cardinal cellular signal of inflammation is the transcription
factor, nuclear factor B (NFB), which induces the transcription
of pro-inflammatory cytokines, adhesion molecules, and enzymes
generating ROS (12, 13). We have previously demonstrated
that glucocorticoids inhibit ROS generation and NFB in MNC in
vivo (14). This action is believed to be the basis of
their anti-inflammatory effect. In this study, we showed that
hydrocortisone at a modest dose of 100 mg given iv induced a rapid fall
in ROS generation by polymorphonuclear leukocytes (PMNL) and
MNC, reduced intranuclear and total cellular NFB and induced IB,
an inhibitor of NFB. These effects are now thought to be the basis
of the anti-inflammatory action of glucocorticoids and other
anti-inflammatory drugs like aspirin (15). In view of the
fact that 1) insulin resistance is associated with increased
atherogenesis (16, 17), 2) troglitazone, a
thiazolidinedione and an insulin sensitizer, has an inhibitory effect
on NFB and other inflammatory mediators (18, 19), and 3)
insulin inhibits NFB in human aortic endothelial cells in
vitro (20), we have now investigated whether insulin
inhibits in vivo: 1) ROS generation and
p47phox subunit by MNC; 2) NFB and stimulates
its inhibitor IB in MNC; and 3) inflammatory mediators, including
soluble intercellular adhesion molecule-1 (sICAM-1), monocyte
chemoattractant protein-1 (MCP-1), and plasminogen activator
inhibitor-1 (PAI-1. This study tests the hypothesis that insulin may
have an anti-inflammatory and, thus, a potential antiatherogenic
effect.
Subjects, Materials, and Methods
Subjects
Ten obese nondiabetic subjects (age range 29–64 yr; mean 48.3 ± 10.9 yr), all with body mass index greater than 37 kg/m2, (body mass index mean 42.6 ± 9.1 kg/m2) were included in this study. All patients had a fasting venous plasma glucose of less than 100 mg/dL. None of the obese subjects was on vitamin E or C or any other antioxidant therapy. There were eight female and two male subjects. Insulin was infused into subjects (2–2.5 IU/h) along with 5% dextrose (100 mL/h) for 4 h. The rate of insulin infusion was titrated such that glucose concentrations were maintained as close to the basal levels as possible. Blood samples were collected at baseline and at 2, 4, and 6 h. Subjects returned after 2–3 weeks and were infused with 5% dextrose (100 mL/h) only or saline (100 mL/h) only for control data. The Institutional Review Board of the State University of New York at Buffalo based at Millard Fillmore Hospital approved the study. Written informed consent was obtained from all subjects.
MNC isolation
Blood samples were collected in Na-EDTA as an anticoagulant. Three and a half milliliters of the anticoagulated blood sample were carefully layered over 3.5 mL of the PMN isolation medium (Robbins Scientific Corp., Sunnyvale, CA). Samples were centrifuged at 450 x g, in a swingout rotor for 30 min at 22 C. At the end of the centrifugation, two bands separate out at the top of the red blood cell pellet. The top band consists of MNC, while the bottom consists of PMNL. The MNC band was harvested with a Pasteur pipette, repeatedly washed with HBSS and reconstituted to a concentration of 4 x 105 cells/mL in HBSS. This method provides yields greater than 95% pure MNC suspension.
NFB electrophoretic mobility shift assay
DNA-binding protein extracts were prepared from MNC by the
method described by Andrews et al. (21). Total
protein concentrations were determined using BCA protein assay
(Pierce Chemical Co., Rockland, IL). NFB gel
retardation assay was performed using NFB-binding protein detection
kit (Life Technologies, Inc., Long Island, NY). Briefly,
the double-stranded oligonucleotide containing a tandem repeat of the
consensus sequence for the NFB-binding site was radiolabeled with
-P32 by T4 kinase. Then 5 µg of the nuclear
extract were mixed with the incubation buffer and the mixture was
preincubated at 4 C for 15 min. Labeled oligonucleotide (60,000 cpm)
was added, and the mixture was incubated at room temperature for 20
min. Samples were then applied to wells of 6% nondenaturing
polyacrylamide gel. The gel was dried under vacuum and exposed to x-ray
film. Densitometry was performed using Bio-Rad Laboratories, Inc. molecular analyst software (Hercules, CA).
Total IB and p47phox subunit Western blotting
MNC cell lysates were prepared by adding 1 mL boiling lysis
buffer (1% SDS), 1 mM sodium ortho-vanadate, 10
mM Tris (pH 7.4) to MNC pellets. Total protein
concentrations were determined using BCA protein assay (Pierce Chemical Co.). Sixty micrograms of total cell lysate were
electrophoresed on 12% for IB or 10% for
p47phox subunit. The proteins were transferred to
polyvinylidene difluoride membrane, blocked for 1 h in 5%
nonfat dry milk and then incubated for 1 h with polyclonal
antibody against IB (Rockland, Gilbertsville, PA) or a
monoclonal antibody against p47phox subunit
(Transduction Laboratories, Inc., San Diego, CA). Finally,
the membrane was washed and developed using super signal
chemiluminescence reagent (Pierce Chemical Co.).
Densitometry was performed using Bio-Rad Laboratories, Inc. molecular analyst software.
ROS generation assay
Respiratory burst activity of MNC was measured by detection of superoxide radical via chemiluminescence. Five hundred milliliters PMNL or MNC (2 x 105 cells) were delivered into a Chronolog Lumi-Aggregometer cuvette to which a spin bar was added. Fifteen milliliters of 10 mM luminol were then added, followed by 1.0 µL of 10 mM formylmethionyl leucinyl phenylalanine. Chemiluminescence was recorded for 15 min (a protracted record after 15 min did not alter the relative amounts of chemiluminescence produced by various cell samples). Our method, developed independently, is similar to that published by Tosi and Hamedani (22). In this assay system, the release of superoxide radical as measured by chemiluminescence, has been shown to be linearly correlated with that measured by the ferricytochrome C method. We further established that, in our assay system, there is a dose-dependent inhibition of chemiluminescence by superoxide dismutase and catalase as well as diphenylene iodonium (data not shown), a specific inhibitor of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, the enzyme responsible for the production of superoxide radicals. The specific inhibitory effect of diphenylene iodonium on NADPH oxidase has been established by Hancock and Jones (23). The variation of ROS generation by MNC in normal or obese subjects varies by less than 8% over a period of 2 weeks.
Plasma sICAM-1, MCP-1, and PAI-1 measurements
Plasma sICAM-1 and MCP-1 were assayed with enzyme-linked immunosorbent assay kits from R&D systems (Minneapolis, MN). Plasma PAI-1 levels were measured using a TintElize PAI-1 kit (Biopool International, Ventura, CA).
Plasma insulin and glucose measurements
Insulin was measured from fasting plasma samples using an enzyme-linked immunosorbent assay kit (Diagnostics Systems Laboratories, Inc., Webster, TX). Glucose was measured in whole blood by a Hemocue glucose analyzer (Hemocue Inc., Mission Viogo, CA).
Statistical analysis
Statistical analysis was performed using SigmaStat software (Jandel Scientific, San Rafael, CA). All data on ROS generation, MCP-1, sICAM-1, and PAI-1 were normalized to a baseline of 100% in view of the interindividual variability and are expressed accordingly as percent of the basal. Kruskal-Wallis one-way ANOVA on ranks was used to compare all the indices measured in this study. Dunnett’s method was used for all pairwise comparisons. The results are expressed as mean ± SE.
Results
Plasma glucose and insulin concentrations
Plasma glucose concentration remained steady during insulin
infusion. Glucose levels were 73 ± 2.3 mg/dL at baseline, 76
± 5.4 mg/dL at 2 h and 73 ± 2.4 mg/dL at 4 h (Fig. 1
). Plasma glucose concentration remained
steady also following dextrose or saline infusion. Plasma insulin
concentrations increased from a basal level of 12.5 ± 2.2 µU/mL
to 28.2 ± 3.3 µU/mL at 2 h and 24.4 ± 3.7 µU/mL at
4 h after insulin infusion (Fig. 2).
Insulin levels decreased after insulin infusion cessation and returned
to basal level (11.3 ± 2.8 µU/mL). Dextrose infusion caused a
slight increase in insulin levels at 2 h and saline infusion alone
did not affect insulin level as shown in Fig. 2.
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B levels. Intranuclear NFB as measured by
electrophoretic mobility shift assay in MNC fell significantly
following insulin infusion at 2 h (64 ± 21% of the basal
level) with a peak inhibitory effect at 4 h 46 ± 22% of the
basal level). Intranuclear NFB reverted toward normal at 6 h
(72 ± 12% of the basal level), but it was still less than that
at baseline (Fig. 3; P <
0.05). Glucose infusion did not cause any change in NFB levels.
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B levels. IB protein levels in MNC increased
significantly to 254 ± 99% at 2 h, peaked at 4 h
(403 ± 266% of the basal level) and declined after stopping
insulin infusion to 366 ± 222% (Fig. 4). The increase was highly significant
(P < 0.001). Dextrose infusion alone did not affect
IB protein levels.
|
). Glucose or
saline infusions did not cause any significant change in ROS generation
by MNC.
|
; P < 0.05). A fall in
p47phox subunit expression was observed in 8 out
of 10 subjects. Neither dextrose nor saline infusion alone changed
p47phox subunit protein levels significantly.
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and 8). MCP-1 levels decreased from a
basal level of 161.4 ± 14.1 pg/mL (100%) to 89.4 ± 9.9%
at 2 h, 79.1 ± 4.8% and 93.0 ± 7.2% at 6 h.
sICAM-1 levels decreased from 292 ± 20 ng/mL (100%) to 85
± 4.7 at 2 h and remained inhibited at 6 h (88 ±
1.4%). It started to increase thereafter at 6 h (92.9 ±
1.4%). The fall in MCP-1 and sICAM-1 was statistically significant as
compared by Kruskal-Wallis one-way ANOVA on ranks (P <
0.05). Neither dextrose nor saline infusion alone caused any
significant changes in plasma MCP-1 or sICAM-1 concentrations.
|
|
. The inhibition of PAI-1 level was
highly significant (P < 0.001). PAI-1 levels did not
change following dextrose or saline infusion alone.
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Our data show for the first time that insulin infusion results in
a fall in NFB and an increase in IB in MNC. These changes are
characteristic of an anti-inflammatory effect at the cellular and
molecular level. NFB is a proinflammatory transcription factor that
leads to the transcription of proinflammatory cytokines and adhesion
molecules and to enzymatic mechanisms that cause ROS generation
(12, 13). IB binds to cytosolic NFB and prevents its
translocation into the nucleus (24, 25). The decrease in
intranuclear NFB, p47phox subunit and the
increase in IB occurred at 2 h and peaked at 4 h. Although
NFB returned to baseline level by 6 h, the increase in IB
persisted even at 6 h. These changes are consistent with an acute
anti-inflammatory effect of insulin and are suggestive that in the long
term, a persistent effect of this kind would indicate a potential
antiatherogenic action of this hormone.
ROS generation by MNC fell in parallel with the fall in NFB. ROS
generation in our system mainly measures the superoxide radical
(O
2), which is formed from molecular oxygen
(O2) by the enzyme NADPH oxidase
(26). Our observations are thus consistent with a
suppression of NADPH oxidase by insulin. Because ROS, including
O2, stimulate NFB mediated inflammation
(27), it is possible that the suppression of O2 contributes to the fall in NFB. NFB also stimulates ROS
generation, induces adhesion molecules and proinflammatory cytokines in
MNC, and thus promotes inflammation (12, 13). The
suppression of NFB would thus reduce ROS generation, the expression
of adhesion molecules and proinflammatory cytokines and reduce
inflammation. Consistent with these changes, the expression of
p47phox subunit, the key protein of the NADPH
oxidase complex (26), falls significantly following
insulin; this is indicative of a fall in NADPH oxidase activity and
O2 generation. It is noteworthy that
p47phox subunit also falls after hydrocortisone
administration in parallel with the fall in ROS generation
(28, 29).
In control experiments conducted with glucose infusions without
insulin, there was a consistently small but insignificant increase in
ROS generation. We have previously described an increase in ROS
generation by leukocytes following a 75-g glucose challenge
(30). Thus, our current observation with a 30-g glucose
challenge over a period of 6 h is consistent with our previous
observation. The small increase in ROS generation induced by glucose
further emphasizes the inhibitory effect of insulin shown by our
experiments. Glucose infusion did not cause a significant change in
NFB or IB levels or p47phox subunit
expression.
It is of interest that these effects of insulin were observed at physiologically relevant concentrations: 28.2 ± 3.3 µU/mL at 2 h and 24.4 ± 3.7 µU/mL at 4 h. These concentrations are comparable to those having effect on hepatic glucose production but are less than those required for glucose uptake by skeletal muscle (31).
We have recently also demonstrated that troglitazone, a
thiazolidinedione, known to be an insulin sensitizer, also causes an
inhibition of ROS generation, an inhibition of NFB, an induction of
IB and a suppression of p47phox subunit
(18, 19). These changes are associated with a fall in
oxidative damage and an improvement in vascular reactivity:
postischemic vasodilatation of the brachial artery (18).
The insulin-induced anti-inflammatory changes described in this paper
are almost identical. Insulin is known to be a vasodilator (32, 33) and exerts this effect through nitric oxide release
(34) and the induction of endothelial nitric oxide
synthase (35). Nitric oxide is also known to have profound
effects on indices associated with inflammation, e.g.,
ICAM-1 (36, 37). Furthermore, insulin causes an inhibition
of ICAM-1 expression by human aortic endothelial cells
(38). It is also of interest that long-term insulin
therapy appears to improve endothelium mediated vasodilatation
(39).
The reduction in ROS generation, O2 in particular, also has
implications for lipid peroxidation since ROS modulate the oxidative
damage to lipids, including low-density lipoprotein (7).
Our observations have implications for our recent demonstration that
glucose intake is associated with a marked increase in ROS generation
and an increase in the expression of p47phox
subunit (30). In that study, we could not decide whether
this was an effect caused by glucose or by insulin. Our present data
show that insulin has an inhibitory effect on ROS generation. Thus, the
marked increase in ROS generation following glucose intake is probably
due to glucose itself rather than endogenous insulin.
The fall in sICAM-1 over the short period of insulin infusion is
consistent with the suppression of intranuclear NFB and the
transcription of proinflammatory adhesion molecules, known to be
modulated by NFB. The rapid fall at 4 h and recovery at 6
h of sICAM-1 suggests a high turnover of sICAM-1. We have recently
demonstrated that insulin suppresses the expression of sICAM-1 by human
aortic endothelial cells in vitro (38);
this indicates that this effect of insulin is a direct one on the
endothelium.
It is relevant that in a recent study, we demonstrated that
troglitazone, an insulin sensitizer of the
thiazolidinedione class of drugs, also causes an increase in IB and
a fall in NFB (both intranuclear and total cellular), as well as a
fall in the proinflammatory cytokine tumor necrosis factor 
and the
chemokine MCP-1 and the proinflammatory adhesion molecule sICAM-1
(19). Troglitazone also caused a reduction in
ROS generation and oxidative damage of lipids and amino acids
(18). Thus, insulin and insulin sensitizers exert an
anti-inflammatory effect that in the long term may prove to be
antiatherogenic.
We have recently described glucocorticoid-mediated changes similar to
those with insulin as described above (14). Thus, an
injection with 100 mg hydrocortisone causes a fall in intranuclear
NFB and an increase in IB. The magnitude of fall in NFB and
the increase in IB were similar after an injection of 100 mg
hydrocortisone as those after insulin infusion were in our experiments.
Thus, insulin appears to exert several of the effects now known to
mediate the anti-inflammatory actions of glucocorticoids. The parallels
between the anti-inflammatory effects of glucocorticoids and insulin
are quite remarkable, considering that glucocorticoids cause
hyperglycemia and increase insulin resistance. Our data would suggest
that the mechanism underlying the induction of insulin resistance and
hyperglycemia by glucocorticoids is distinct from the anti-inflammatory
effects of these drugs.
The acute anti-inflammatory effects of insulin may explain at least in part the benefits observed previously with insulin-glucose infusion treatment in patients with acute myocardial infarction as observed in the Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction study (40). It has hitherto been believed that insulin improves the metabolic state of patients by inhibiting lipolysis and reducing FFA concentrations. FFAs produce a prothrombotic state (41). Our study warrants future investigation on the potential anti-inflammatory effect of insulin infusions in patients with acute coronary syndromes. Whether a part of this effect is exerted through FFA inhibition and whether FFAs exert a proinflammatory effect requires further investigation.
Our observations also bear relevance to the use of insulin in the treatment of type 2 diabetes. In view of the association of hyperinsulinemia and insulin resistance to type 2 diabetes and the fact that type 2 diabetics experience accelerated atherosclerosis and its clinical complications (16, 42), it has been suggested that treatment with exogenous insulin may promote further hyperinsulinemia and may promote further the cardiovascular risk (43, 44). Our data on the anti-inflammatory effect of insulin provide a challenge to this concept and suggest that insulin therapy may actually be potentially beneficial. Indeed, a recent paper by Vehkavaara et al. (39) shows that chronic insulin therapy may improve endothelium mediated vasodilatation. Furthermore, the United Kingdom prospective diabetes study, conducted over a protracted period, produced no evidence that insulin produced an increase in the incidence of atherosclerosis related complications (45).
Although our current observations were obtained in obese insulin resistant subjects, it is likely that insulin also exerts similar effects in normal subjects; indeed, our preliminary data demonstrate this. This fact raises questions about the mechanisms underlying the similarities in the actions of insulin and thiazolidenediones; these issues require further elucidation. These issues need to be addressed especially because obese patients are known to have increased oxidative damage (46) and also have evidence of increased C-RP (47), an index of inflammation.
Our observations also raise questions about new targets of insulin action. The circulating MNC are known to have insulin receptors (48) and the question of whether insulin promotes glucose uptake by these cells has been debated. It would appear that insulin probably exerts, hitherto, unknown and unexpected effects on the MNC. Although our study does not rule out the possibility that insulin may exert those effects through another mediator, in vivo, it is possible that it is a direct effect. The pharmacodynamics of this anti-inflammatory effect is similar to those of glucocorticoids.
In conclusion, our data demonstrate for the first time an acute
stimulatory effect on IB expression by MNC and suppressive actions
of insulin on NFB, ROS generation and p47phox
subunit. Furthermore, insulin inhibits sICAM-1, MCP-1, and PAI-1
concentrations. These actions, similar to those of glucocorticoids, are
consistent with an acute anti-inflammatory effect of insulin and
therefore, are suggestive of a potential antiatherogenic effect of this
hormone in the long term.
Acknowledgments
We acknowledge the support from William G. McGowan Charitable Fund, Inc. and thank Pamela Maher for the preparation of this manuscript.
Received September 11, 2000.
Revised January 24, 2001.
Accepted March 9, 2001.
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