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A1CR
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Joined: 18 Jan 2006
Posts: 559
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 Posted: Wed Jan 18, 2006 5:21 pm Post subject: Weight loss, inflammatory proteins and insulin resistance... |
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Here's a study from 2003 of 37 patients, 4 males, who went
from an average of 136 to 92 for BMI. Their inflammatory
proteins were strongly affected -- this correlated with
insulin resistance syndrome. Especially affected was the
association between the glucose level and interleukin-6.
The study on CRONers was I believe going to involve
examining interleukin-6 levels in blood immune cells from
the CRONers. That glucose response in terms of fasting
level and effect of glucose loading was so greatly
associated with the inflammatory proteins is consistent with
the observations of Fontana/Holloszy that certain CRONies'
glucose went to high in the the study at Washington
University (St. Louis).
Kopp HP, Kopp CW, Festa A, Krzyzanowska K, Kriwanek S, Minar
E, Roka R, Schernthaner G.
Impact of weight loss on inflammatory proteins and their
association with the insulin resistance syndrome in morbidly obese patients.
Arterioscler Thromb Vasc Biol. 2003 Jun 1;23(6):1042-7. Epub
2003 Apr 24.
| Quote: |
OBJECTIVE:
Obesity is closely linked to the insulin resistance syndrome
(IRS), type 2
diabetes, and cardiovascular disease, the primary cause of
morbidity and
mortality in these patients. Elevated levels of C-reactive
protein (CRP) and
interleukin-6 (IL-6), indicating chronic subclinical
inflammation, have been
associated with features of the IRS and incident
cardiovascular disease.
METHODS AND RESULTS:
We studied the cross-sectional and longitudinal relation of
CRP, IL-6, and
tumor necrosis factor-alpha (TNF-alpha) with features of the
IRS in 37
morbidly obese patients with different stages of glucose
tolerance before
and 14 months after gastric surgery. Weight loss after
gastric surgery
induced a significant shift from diabetes (37% vs 3%) to
impaired glucose
tolerance (40% vs 33%) and normal glucose tolerance (23% vs
64%). The
baseline concentration of IL-6 was correlated with TNF-alpha
(r=0.59,
P<0.01) and CRP (r=0.44, P<0.05) levels. TNF-alpha, IL-6,
and CRP were
significantly correlated with insulin resistance estimated
by the
homeostatic model assessment (r=0.48, P<0.05; r=0.56,
P<0.01; and r=0.35,
P<0.05, respectively). Concentrations of CRP and IL-6
decreased after weight
loss (median, 8.6 and interquartile range, 2.7/14.5 vs 2.5
and 1.2/4.1 mg/L;
P<0.006, and 5.13 and 2.72/12.15 vs 3.95 and 1.97/5.64
pg/mL, P<0.02,
respectively), whereas serum levels of TNF-alpha remained
unchanged (8.6 and
6.3/18.8 vs 11.7 and 5.8/17.2 pg/mL; NS.). Multiple
regression analysis
revealed that the decrease in insulin resistance remained
independently and
significantly correlated with the decrease in IL-6
concentrations (P<0.01)
and the decrease in body mass index with the decrease in CRP
(P<0.05),
respectively.
CONCLUSIONS:
Weight loss in morbidly obese patients induces a significant
decrease of CRP
and IL-6 concentrations in association with an improvement
of the IRS.
PMID: 12714437 [PubMed - in process]
Insulin resistance and type 2 diabetes are closely related
to the body mass
index (BMI), a marker of overall obesity. 1 Obesity is
associated with an
increased risk of coronary heart disease, stroke,
hypertension, type 2
diabetes mellitus, dyslipidemia, and all-cause mortality.
2,3 A BMI >35
kg/m2 increases insulin resistance, hyperinsulinemia, and
hyperglycemia, 4–8
thus leading to an increased risk for diabetes by >60-fold
in women and
42-fold in men. 9 The insulin resistance syndrome (IRS) is
associated with a
high cardiovascular risk 10 and is the major cause of death
in patients with
type 2 diabetes. 11
However, pathophysiological mechanisms linking adiposity
with insulin
resistance and eventually cardiovascular disease remain
largely elusive. One
mechanism might be the enhanced production of adipose
tissue–derived
proteins, such as interleukin-6 (IL-6) and tumor necrosis
factor-[alpha]
(TNF-[alpha]). 12,13 Elevated levels of C-reactive protein
CRP) and IL-6,
indicating chronic subclinical inflammation, have been
associated with
features of the IRS 14,15 and incident cardiovascular
disease, including
myocardial infarction, stroke, and peripheral vascular
disease. 16-20 Weight
control is a widely accepted and recommended clinical goal
in patients with
type 2 diabetes and obesity. 1 The impact of weight loss on
mortality and
morbidity, in particular from cardiovascular disease, is
still a matter of
debate. 21 Studies investigating the impact of weight loss
on cardiovascular
end points as well as various surrogate markers of
cardiovascular disease
are of particular interest. Morbidly obese subjects and
their marked weight
loss after gastroplastic surgery emerge as a valuable model
for studying the
impact of changes in body weight and the associated
cardiovascular risk
factors.
We therefore investigated the relation of circulating
levels of
inflammatory proteins, including CRP and IL-6, to features
of the IRS
cross-sectionally and also longitudinally in morbidly obese
diabetic and
nondiabetic subjects undergoing gastroplastic surgery.
Methods
Patients
Thirty-seven severely obese patients selected to undergo
gastroplastic
surgery participated in the study. Clinical characteristics
of the study
participants are shown in Table 1. Surgery had been
indicated according to
the guidelines of the National Institutes of Health
consensus statement for
surgery in severe obesity. 22 Patients were systematically
referred to a
multidisciplinary team for medical, psychological,
nutritional, and surgical
expertise. Surgery was indicated for patients with a history
of repeated
failures with conservative nonsurgical techniques and whose
BMI was >40
kg/m2. None of the subjects had a history of stroke,
transient ischemic
attack, myocardial infarction, angina pectoris, or
electrocardiographic
abnormalities. Patients with overt eating disorders, heavy
alcohol
consumption, major psychiatric disease, hepatic or renal
failure, Cushing
syndrome, thyroid dysfunction, or other major endocrine
disorders were
excluded. Patients with clinically overt infectious diseases
were omitted
from the study. All subjects were carefully instructed about
the aims of the
study, and written, informed consent was obtained.
TABLE 1. Clinical and Metabolic Parameters of Morbidly
Obese Patients
Before and 14
Months After Gastroplastic Surgery
Changes in Dietary Intake, Exercise Habits, and Medication
Dietary changes after vertical banded gastroplasty were
similar to those
that we have previously reported. 23 Postoperatively, all
patients were
instructed to use a cycle for at least 20 minutes a day.
None of the
patients were taking statins or fibrates before or after
surgery. Nine of 37
patients were taking angiotensin-converting enzyme
inhibitors; 2,
[beta]-blockers; and 2, calcium channel blockers. In total,
10 patients were
treated with antihypertensive drugs before surgery, 1
patient received
sulfonylurea, and 3 received metformin. Postoperatively
antihypertensive and
antidiabetic drug treatments could be stopped.
Methods
Insulin resistance was estimated from fasting glucose and
insulin
concentrations with the homeostatic model assessment (HOMA
Preoperative and postoperative clinical and metabolic
characteristics of
patients are shown in Table 1. Weight loss induced by
gastric surgery caused
a significant shift from diabetes (37% vs 3%) to IGT (40% vs
33%) and NGT
(23% vs 64%;P <0.0001). Fasting,
1-hour, and 2-hour blood glucose and insulin levels, as
well as BMI, blood
pressure, and triglycerides, were significantly reduced 14
months after surgery (Table 1).
Effect of Weight Loss on Proinflammatory Proteins Serum CRP
Concentrations
Serum concentrations of CRP (median, 8.6; interquartile
range, 2.7/14.5 vs
2.5 and 1.2/4.1 mg/L, respectively;P <0.006) and IL-6 (5.13
and 2.72/12.15
vs 3.95 and 1.97/5.64 pg/mL, respectively;P <0.02) were reduced
significantly, whereas levels of TNF-[alpha] remained
unchanged (8.6 and
6.3/18.8 vs 11.7 and 5.8/17.2 pg/mL, respectively; NS;Figure 1).
Preoperatively, patients with type 2 diabetes (n=14) and IGT
(n=16) showed
higher levels of CRP than did subjects with NGT (n=7), but
postoperatively,
these levels were comparable between groups (Table 2). In
patients with type
2 diabetes, levels of IL-6 were twice as high compared with
NGT, both
preoperatively and postoperatively (Table 2). Concentrations
of TNF-[alpha]
showed no differences between groups and did not decrease
after weight loss.
The 95% confidence intervals of the mean post-minus-pre
differences are
(-10, -2), (-6.4, -0.7), and (-6.7, 2.5) for CRP, IL-6, and
TNF-[alpha],
respectively.
Association of the IRS With Proinflammatory Proteins
Correlation analysis at baseline of TNF-[alpha], CRP, and
IL-6 and
features of the IRS are shown in Table 3. The preoperative
concentration of
IL-6 was more closely related to glycemia (glucose levels
during OGTT,
glycosylated hemoglobin), whereas the concentration of CRP
was more closely
correlated to glucose-stimulated insulin release. All
inflammatory markers
(TNF-[alpha], IL-6, and CRP) were significantly correlated
with insulin
resistance as estimated by HOMA. To further explore the
relation between CRP
and insulin as well as IL-6 and glucose, patients were
stratified into 2
groups according to the baseline median cutoff levels of CRP
(8.5 mg/L) and
IL-6 (5.13 pg/mL). Subjects with low IL-6 concentrations had
significantly
lower levels of blood glucose in the OGTT at baseline than
did subjects with
high levels of IL-6 (fasting, 103±17 vs 141±79 mg/dL, NS; 1
hour, 160±51 vs
249±111 mg/dL, P <0.01; 2 hour, 117±38 vs 191±108 mg/dL, P
<0.02). Patients
within the high-CRP group at baseline had a significantly higher
glucose-stimulated insulin concentration than did patients
within the
low-CRP group (fasting, 34±19 vs 19±8 µU/mL, P <0.01; 1
hour, 153±75 vs
89±53 µU/mL, P <0.01; 2 hour, 115±69 vs 50±35 µU/mL, P
<0.003). Patients
with initially high CRP levels showed a significantly larger
decrease in
insulin concentrations during weight loss than did patients
with low CRP
values (fasting insulin, 19±15 vs 8±8.2 µU/mL, P <0.02; 1
hour, 94±81 vs
27±38 µU/mL, P <0.008; 2 hour, 84±77 vs 27±30 µU/mL, P
<0.02). The decrease
in IL-6 concentration was significantly correlated with
decrease in
TNF-[alpha], blood glucose (fasting, 1 hour, and 2 hour),
C-peptide,
glycosylated hemoglobin, and insulin resistance, as
estimated by HOMA (Table
4). The decrease in CRP was correlated with the decrease in
metabolic
parameters like BMI, 2-hour blood glucose, 1-hour insulin
levels, and
C-peptide (Table 4). Multiple linear regression analyses
were performed to
further assess the relation of the changes in IL-6 and CRP
concentrations to
the changes in variables of the IRS. Independent variables
in the models
were those that were significantly correlated with IL-6 and
CRP in
univariate analysis (Table 4). After adjusting for fasting
blood glucose,
glycosylated hemoglobin, and C-peptide, only the decrease in
insulin
resistance remained independently and significantly
associated with the
decrease in IL-6 concentration (P <0.01). In a similar model
including the
change in BMI, 1-hour insulin, HOMA, and C-peptide as
independent variables,
only the change in BMI was significantly related to the
decrease in CRP (P
<0.05). In a model exploring TNF-[alpha] as a dependent
variable, none of
these variables were significantly related with the change
in the
concentration of TNF-[alpha].
Discussion
In the present study, we have shown a significant
reduction in circulating
CRP and IL-6 levels after weight loss after gastroplastic
surgery in
morbidly obese individuals. The decrease in inflammatory
markers was related
to improvement in insulin resistance, body-weight, and glycemia.
Accordingly, a significant and impressive shift toward
normalized glucose
tolerance status was seen, with a reversal of overt type 2
diabetes in all
subjects but 1.
In line with previous reports, we have shown an association
between
inflammatory proteins and parameters of the IRS by
cross-sectional analysis.
14,15,27–29 However, only limited data are available about
the longitudinal
effects of weight loss. In a study with 21 obese women, no
significant
decrease in CRP after weight loss after 3 weeks was
observed, 30 probably
because of the small number of subjects and a relatively
modest weight loss
of [almost equal to]3 kg. Heilbronn et al 31 report elevated
levels of CRP
in obese but otherwise healthy female subjects, which
declined during weight
loss of [almost equal to]7 kg during a very-low-calorie
diet. In another
study, a significant decrease in CRP was shown in 25 obese,
postmenopausal
women completing a weight loss program with a reduction of
14 kg of body
weight. 32 However, because no measurements of IL-6 and
TNF-[alpha] were
made in the latter studies, it remains speculative whether
the increased
concentration of CRP in these obese subjects was due to IL-6, as
hypothesized.
Recently, in a study conducted with 20 obese women
undergoing gastric
banding, a decrease in CRP levels was found 1 year after
surgery (mean
weight loss, 30 kg), but TNF-[alpha] levels remained
unchanged and IL-6
levels moderately increased. 33 Finally, Ziccardi et al 34
showed decreased
IL-6 as well as TNF-[alpha] levels after a 1-year,
multidisciplinary, weight
reduction program (mean weight loss of 9.8 kg) in 56 healthy
premenopausal,
obese, nondiabetic women.
Taken together, the results of these studies, along with
the results of the
present study, suggest that weight loss results in decreased
circulating
levels of CRP. On the other hand, apparently conflicting
results are
reported on the effect of weight loss on levels of IL-6 and
TNF-[alpha].
33,34 Baseline differences in the study populations (eg,
glucose tolerance
status or insulin resistance) might explain the differing
results. In the
present study, IL-6 was closely related to glycemia;
however, a significant
number of subjects had diabetes, whereas in the study of
Laimer et al, 33
only 1 and in the study of Ziccardi et al, none had
diabetes. In addition to
weight loss, the substantial change in dietary intake after
gastroplasty
might have contributed to the observed change in the
concentrations of CRP
and IL-6.
In multivariate analyses, the change in IL-6 was related to
the change in
insulin resistance, whereas the change in CRP was
independently related to
the change in BMI. Therefore, an intervention that might
affect insulin
resistance, glycemia, or body weight to a different degree
might also affect
CRP and IL-6 levels differently. In addition, the plasma
half-life of IL-6
is <6 hours and thus, considerably less than the half-life
of CRP 14;
therefore, CRP might provide a more stable indicator of
subclinical
inflammation than IL-6. Finally, it is interesting to note
that treatment
with an insulin-sensitizing peroxisome proliferator-activated
receptor-[gamma] agonist beneficially affected CRP but not
IL-6 levels in
patients with type 2 diabetes, also suggesting differential
effects of
therapeutic interventions on CRP and IL-6 levels. 35 A
significant
interrelation of inflammatory proteins, including IL-6, CRP, and
TNF-[alpha], has been shown in the present study as well as
in previous
reports. 27 Inflammatory proteins have been related to body
weight 31 and
insulin resistance. 15 The present longitudinal study
supports the view that
adipose tissue, insulin resistance, and “proinflammatory
cytokines” are part
of an interrelated network that might eventually result in
cardiovascular
disease. The association of inflammatory markers with
adipose tissue is
supported by experimental and clinical evidence. In vivo
experiments have
demonstrated IL-6 mRNA expression on, as well as IL-6
release from, human
adipose tissue. 12,36
IL-6 production derived from adipose tissue accounts for
[almost equal
to]20% to 30% of total IL-6 serum levels and is increased in
adiposity.
27,36 Obese patients have significantly higher serum
concentrations of
inflammatory proteins than do lean controls. 37 IL-6 is a
powerful inducer
of acute-phase proteins, such as CRP. 38 Epidemiological
studies have shown
a relation of CRP and IL-6 to measurements of the IRS,
15,27,39,40 including
BMI. Similar relations were found in the present study.
Inflammatory
proteins have also been related to measures of insulin
resistance in the
present study, as well as in previous reports. 15,27,40 To
our knowledge,
this is the first study to show, by multivariate analysis, a
significant
correlation of changes in IL-6 with changes in insulin
resistance measured
by HOMA and of changes in CRP with changes in BMI after
weight loss. The
clinical relevance of CRP lowering associated with massive
weight loss in
morbidly obese patients has to be investigated in future
studies. Although
no specific drug treatment to reduce CRP values is
available, both statins
41,42 and aspirin 43,44 attenuate the risk of coronary heart
disease in
individuals with
increased CRP.
In the present study, we could demonstrate an impressive
reduction in the
levels of CRP and IL-6 by as much as 81% and 23%,
respectively, compared
with baseline levels. Interestingly, a doubling of CRP or
IL-6 levels was
found to be associated with a doubling in the risk for
myocardial infarction
in apparently healthy men. 14,19 By analogy, it seems likely
that a
significant reduction in CRP and IL-6 levels associated with
weight loss
could also reduce the cardiovascular risk in morbidly obese
patients.
In summary, we have shown a marked decrease in circulating
levels of
inflammatory markers in association with a reversal of
diabetes in morbidly
obese individuals after gastroplastic surgery. Long-term
studies are needed
to show whether this improvement in cardiovascular risk
factors will
eventually translate into a significant clinical benefit in
regard to
cardiovascular morbidity and mortality. |
Date: Sat, 28 Jun 2003 08:47:38 -0230 [AP] |
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