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Original Studies |
Are Increased in Obese Patients with Noninsulin-Dependent Diabetes Mellitus1
Third Department of Internal Medicine (A.K., Y.S., K.I., M.F., K.T., H.G., K.N., Y.Y.) and Department of Radiology (S.M.), Mie University School of Medicine; Department of Internal Medicine (K.M., Y.T.), Yamada Red Cross Hospital, Mie, Japan
Address correspondence and requests for reprints to: Akira Katsuki, M.D., Third Department of Internal Medicine, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie 514, Japan.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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(TNF-) in the mechanism of insulin resistance, we studied
12 obese patients with noninsulin-dependent diabetes mellitus (NIDDM).
We evaluated the relationship of TNF- levels with the visceral,
subcutaneous, and total fat areas measured by computed tomography (CT),
and with insulin resistance evaluated by the glucose infusion rate
(GIR) observed during an euglycemic hyperinsulinemic clamp study.
Controls consisted of 12 normal subjects and 12 nonobese patients with
NIDDM. TNF- levels were measured using a high sensitivity
enzyme-linked immunosorbent assay. Following admission, all patients
with NIDDM participated in a 4-week program of diet and exercise. After
this treatment, we evaluated the relationship of the serum levels of
TNF- with the area of body fat, the GIR, and the resultant change in
the TNF- level.
Serum levels of TNF- in the obese patients with NIDDM significantly
exceeded those observed in normal subjects (P < 0.01)
or in the nonobese patients with NIDDM (P < 0.01).
Serum levels of TNF- in obese NIDDM patients showed a significant
positive correlation with the area of visceral fat before (r =
0.662, P < 0.03) and after (r = 0.508,
P < 0.05) the treatment; similar correlation was
observed in all patients with NIDDM before (r = 0.537,
P < 0.02) and after (r = 0.430, P
< 0.05) the treatment. Serum levels of TNF- in obese NIDDM patients
showed a significant negative correlation with GIR after the treatment
(r = -0.595, P < 0.05). Serum levels of TNF-
were significantly reduced in the obese patients with NIDDM after the
treatment (P < 0.01), while those in the nonobese
NIDDM patients were unchanged.
These results suggest that serum TNF- levels may play an important
role in mechanism of insulin resistance associated with obesity.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Tumor necrosis factor- (TNF-) was reported to inhibit insulin
action and to play a role in insulin resistance in obesity (2, 3, 4, 5).
Previous investigators speculated that the overexpression of TNF- in
adipose tissue would inhibit the transport of glucose in an autocrine
or paracrine fashion. Until recently, blood levels of TNF- could not
be accurately measured because sensitive assays for TNF- were not
available (6).
In the present study, we measured the serum levels of TNF- in obese
and nonobese patients with NIDDM using a high-sensitive system, and we
determined their relationship with the area of body fat measured by
computed tomography (CT) and with the glucose infusion rate (GIR)
evaluated by the euglycemic hyperinsulinemic clamp technique.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We evaluated 12 patients with obesity (body mass index: BMI
> 26.4) and NIDDM (obese group). Data obtained in 12 normal subjects
(normal group) and 12 nonobese NIDDM patients (nonobese group) served
as controls. The age, gender, fasting plasma glucose level,
HbAIc level, and duration of diabetes mellitus in the
control group were matched with those of the obese group (Table 1
). Patients with NIDDM that participated
in this study were physical workers with night duty in factories. They
did not have any complaint and were found to have NIDDM during a group
medical examination. We also evaluated the serum TNF- levels in 8
obese male subjects without NIDDM (age; 49.10 ± 2.29; BMI,
27.20 ± 0.20).
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No abnormality in the 75-g OGTT was found in the group of normal subjects. None of the normal subjects reported any change in body weight before the investigation.
Each subject underwent physical and laboratory investigations to exclude the presence of systemic inflammatory disease. Informed consent was obtained from each subject before the study admission.
Study protocol and methods
Blood samples were drawn from each subject before breakfast in
the early morning, after an overnight bed-rest. TNF- in serum
samples was measured using a commercially available sandwich
immunoassay kit (Quantikine HS Human TNF- immunoassay kit, R&D
systems, Minneapolis, MN) and following the manufacturer’s
instructions. Briefly, 200 µL of standard or serum samples were added
to microtiter plate wells coated with a monoclonal antibody specific
for TNF-, followed by incubation at 4 C for 16 h. The wells
were then washed 4 times with a buffered surfactant solution, and
thereafter, 200 µL of anti-TNF- polyclonal antibody conjugated to
alkaline phosphatase were added to each well and incubated for 3 h
at room temperature. After appropriate washing, 50 µL of substrate
solution (NADPH) were added to each well and incubated again for 60 min
at room temperature. After this, 50 µL of amplifier enzyme solution
were added to the well, followed by incubation for 30 min at room
temperature. The reaction was then stopped by the addition of 2N
sulfuric acid to the wells, and absorbance was measured at 490 nm with
corrections set at 650 nm using a microplate reader. The values of
serum TNF- levels were extrapolated from a curve drawn using
standard TNF-. The minimum detectable concentration by this assay
was 0.01 pmol/L, and the intra- and interassay coefficients of
variation of the assay were 5.6% and 7.5%, respectively. No
significant cross-reactivity or interference with other factors related
to TNF- or other cytokines was observed. The precision of the
TNF- assay using the above described immunoassay is better than that
of other methods previously reported. Previous methods showed TNF-
minimum detection levels of 0.24 pmol/L. The plasma glucose level was
measured by an automated enzymatic method. The HbAIc
(normal value: 4.3–5.8%) was measured by high performance liquid
chromatography (HPLC). Serum insulin was measured using an
immunoradiometric assay kit (DAINABOT Corp., Tokyo, Japan). Blood
pressure was determined in supine position after a 5-min rest.
After admission, the patients with NIDDM participated in a program of
diet and exercise for about 4 weeks. The dietary treatment was as
follows: 1400–1720 kcal/day with a diet consisting of 20 energy
percent (en %) protein, 25 en % fat, and 55 en % carbohydrates. As
exercise therapy, the patients walked about 15,000 steps daily, as
counted by a pedometer. Serum TNF- level, body fat area, and insulin
sensitivity were measured in each subject before and after the
initiation of treatment. The body fat area was evaluated by a
previously described method (7). The total cross-sectional area, the
intra-abdominal visceral fat, and the subcutaneous fat areas were
measured by abdominal computed tomography (CT) taken at the umbilical
level. Any intraperitoneal region having the same density as the
subcutaneous fat layer was defined as a visceral fat area. Insulin
sensitivity was evaluated by the euglycemic hyperinsulinemic clamp
technique using the artificial pancreas (STG-22, NIKKISO, Tokyo, Japan)
(8). The clamp study was performed for 120 min, and the desired level
of serum insulin was fixed to 1200 pmol/L. The mean values of insulin
reached a stable level between 90 min and 120 min after starting the
clamp study (obese group before treatment: 1186.45 ± 43.42
pmol/L, after treatment: 1195.45 ± 57.48 pmol/L, nonobese group
before treatment: 1188.30 ± 54.76 pmol/L, after treatment:
1111.02 ± 32.65 pmol/L). The blood glucose was clamped to desired
level (5.24 mmol/L), and the mean amount of glucose administered in the
last 30 min was regarded as the glucose infusion rate (GIR).
Statistical methods
Data are expressed as the mean ± SE.
Comparison between groups was done using the Mann-Whitney U test. The
statistical difference between TNF- levels before and after
treatment was analyzed by the Wilcoxon’s rank sum test. The strength
of correlation between variables was calculated using Spearman’s rank
correlation. A level of P less than 0.05 was accepted as
statistically significant.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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were not statistically different
between the normal and nonobese groups. Subjects of the obese group
presented significantly higher serum concentrations of TNF- than
those of the normal (P < 0.01) and nonobese
(P < 0.01) groups (Fig. 1). Serum TNF- levels (1.89 ±
0.26 pmol/L) in 8 obese subjects without NIDDM were significantly
elevated compared with those in the normal (P < 0.01)
and nonobese (P < 0.01) groups. However they were not
significantly different compared with those in the obese group.
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.
There was no significant difference between the obese and nonobese
groups in the levels of fasting plasma glucose and HbAIc
after treatment. Serum TNF- levels in the obese group significantly
decreased after treatment (P < 0.01), but no
significant change was observed in the nonobese group (Fig. 2).
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were positively
correlated with the visceral fat area before (r = 0.662,
P < 0.03) and after (r = 0.508, P
< 0.05) the treatment. There was also a significant positive
correlation between serum levels of TNF- and visceral fat area
before (r = 0.537, P < 0.02) and after (r =
0.430, P < 0.05) the treatment in all patients with
NIDDM, including obese and nonobese subjects (Fig. 3). Serum levels of TNF- were not
significantly correlated with the subcutaneous fat area or total fat
area, either before or after the treatment, in all and in obese
patients with NIDDM.
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levels and the GIR in obese patients with
NIDDM (r = -0.595, P < 0.05) (Fig. 4).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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is significantly increased
in NIDDM patients with obesity. In obese patients with NIDDM, the serum
levels of TNF- were significantly correlated with visceral
adiposity, and it was applicable to all (obese and nonobese) patients
with NIDDM. However, it is worthy to note that the obese subjects of
the present study were not typically obese subjects. The observation of
increased intraperitoneal fat accumulation indicated that they have
visceral fat type of obesity (9, 10). Our NIDDM patients had increased
visceral fat, but without significant increase in their total body fat.
Nevertheless, the results of the present study in obese NIDDM subjects
would probably not be observed in typical obese subjects. Namely,
although in our present study the serum TNF- levels were
significantly correlated only with the visceral fat area, they might
also be significantly correlated with the subcutaneous fat area and
with the total fat area in typically obese patients with NIDDM.
The elevation of the serum levels of TNF- significantly decreased
after treatment in obese subjects with NIDDM but not in the nonobese
group. A lesser degree of fatty tissue decrease in the nonobese group
than in the obese group may be a potential explanation for this
finding. The decrease in the accumulation of fatty tissues in the
nonobese group after the treatment was probably insufficient to produce
a significant change in the serum levels of TNF-. These results
suggest that increased total body fat may be an important factor in the
regulation of serum TNF- levels.
On the other hand, previous studies have shown that hyperglycemia or
the presence of diabetes mellitus may enhance the production of TNF-
from monocytes in vitro (11, 12). Our present results
suggest that hyperglycemia does not affect the serum levels of
TNF-.
The association between insulin resistance and TNF- has been
previously reported (13, 14, 15, 16, 17, 18, 19, 20, 21, 22). In the current study, we found that the
serum levels of TNF- are inversely correlated with GIR in obese
NIDDM patients after, but not before, the treatment. The lack of
correlation between the serum TNF- levels and GIR before the
treatment was probably the result of the influence of obesity and
glucose toxicity on GIR. Kroder et al. (23) reported that
the mechanism of insulin resistance caused by TNF- differs from that
induced by hyperglycemia. Our results suggest that serum TNF- levels
may play an important role in the mechanism of insulin resistance
associated with obesity. The serum levels of TNF- found in the
present study were relatively low, and circulating TNF- may not be
biologically active at such low concentration. However, it is probable
that locally produced TNF- may act synergistically with circulating
TNF- on fatty and muscular tissues.
In conclusion, our results suggest that serum TNF- levels are
influenced by body fat accumulation and that they may contribute to the
insulin resistance associated with obesity.
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Acknowledgments |
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Footnotes |
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Received January 14, 1997.
Revised March 28, 1997.
Revised June 3, 1997.
Accepted November 12, 1997.
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 A. E. Hak, C. D. A. Stehouwer, M. L. Bots, K. H. Polderman, C. G. Schalkwijk, I. C. D. Westendorp, A. Hofman, and J. C. M. Witteman Associations of C-Reactive Protein With Measures of Obesity, Insulin Resistance, and Subclinical Atherosclerosis in Healthy, Middle-Aged Women Arterioscler Thromb Vasc Biol, August 1, 1999; 19(8): 1986 - 1991. [Abstract] [Full Text] [PDF]
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 T. Sakamoto, J. Woodcock-Mitchell, K. Marutsuka, J. J. Mitchell, B. E. Sobel, and S. Fujii TNF-alpha and insulin, alone and synergistically, induce plasminogen activator inhibitor-1 expression in adipocytes Am J Physiol Cell Physiol, June 1, 1999; 276(6): C1391 - C1397. [Abstract] [Full Text] [PDF]
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K. T. Uysal, S. M. Wiesbrock, and G. S. Hotamisligil Functional Analysis of Tumor Necrosis Factor (TNF) Receptors in TNF-{alpha}-Mediated Insulin Resistance in Genetic Obesity Endocrinology, December 1, 1998; 139(12): 4832 - 4838. [Abstract] [Full Text] [PDF]
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, Obese NIDDM; •, nonobese
NIDDM.