Advancing age and insulin resistance: role of plasma tumor
necrosis factor-
Giuseppe
Paolisso1,
Maria
Rosaria
Rizzo1,
Gherardo
Mazziotti2,
Maria Rosaria
Tagliamonte1,
Antonio
Gambardella1,
Mario
Rotondi2,
Carlo
Carella2,
Dario
Giugliano1,
Michele
Varricchio1, and
Felice
D'Onofrio1
1 Department of Geriatric
Medicine and Metabolic Diseases and
2 Institute of
Endocrinology-II, University of Napoli, 80138 Naples, Italy
 |
ABSTRACT |
In 70 healthy
subjects with a large age range, the relationships between plasma tumor
necrosis factor-
(TNF-
) and body composition, insulin action, and
substrate oxidation were investigated. In the cross-sectional study
(n = 70), advancing age correlated
with plasma TNF-
concentration (r = 0.64, P < 0.001) and whole body glucose disposal (WBGD; r=
0.38, P < 0.01). The
correlation between plasma TNF-
and age was independent of sex and
body fat (BF; r = 0.31, P < 0.01). Independent of age and
sex, a significant relationship between plasma TNF-
and leptin
concentration (r = 0.29, P < 0.02) was also found. After
control for age, sex, BF, and waist-to-hip ratio (WHR), plasma TNF-
was still correlated with WBGD (r =
0.33, P < 0.007). Further
correction for plasma free fatty acid (FFA) concentration made the
latter correlation no more significant. In a multivariate analysis, a
model made by age, sex, BF, fat- free mass, WHR, and plasma TNF-
concentrations explained 69% of WBGD variability with age
(P < 0.009), BF
(P < 0.006), fat-free mass
(P < 0.005), and plasma TNF-
(P < 0.05) significantly
and independently associated with WBGD. In the longitudinal study, made
with subjects at the highest tertiles of plasma TNF-
concentration
(n = 50), plasma TNF-
concentration
predicted a decline in WBGD independent of age, sex, BF, WHR
[relative risk (RR) = 2.0; 95% confidence intervals (CI) = 1.2-2.4]. After further adjustment for plasma fasting FFA
concentration, the predictive role of fasting plasma TNF-
concentration on WBGD (RR = 1.2; CI = 0.8-1.5) was no
more significant. In conclusion, our study demonstrates that plasma
TNF-
concentration is significantly associated with advancing age
and that it predicts the impairment in insulin action with advancing
age.
insulin action; substrate oxidation
 |
INTRODUCTION |
THE RELATIONSHIP between advancing age and impaired
insulin action is well known (11, 29). Recently, tumor necrosis
factor-
(TNF-
) has been implicated in the development of insulin
resistance (8, 19, 20, 34) and, therefore, in the pathogenesis of obesity (27, 32) and non-insulin-dependent diabetes mellitus (NIDDM)
(1, 17). With regard to age, studies in mice have already shown plasma
TNF-
concentration to increase with advancing age (3, 15, 26);
nevertheless, data in humans are lacking. Age-related increase in body
fatness might be responsible for an increase in plasma TNF-
concentration, which in turn might contribute to derange insulin action
in the elderly.
Recently, leptin, the product of the
ob/ob gene (35), has been considered a
further potential candidate as a fat tissue-dependent mediator causing
insulin resistance (22). If a cross talk between adipose tissue and
skeletal muscle is mediated by TNF-
or leptin, an endocrine
mechanism involving circulating TNF-
and leptin is conceivable. In
light of such a possibility, a correlation among plasma TNF-
and
leptin concentrations and insulin sensitivity should be found.
Unfortunately, data on such associations are contrasting (14, 21).
Furthermore, no study in a large sample of aged subjects has been made.
In light of such experimental evidence, we asked the following
questions. 1) Does an age-related
increase in plasma TNF-
concentration occur in humans? If the answer
to this question is yes, 2) does
plasma TNF-
concentration affect age-related insulin resistance?
Finally, 3) is there any
relationship between fasting plasma TNF-
and leptin concentrations
in humans? To answer these questions, plasma TNF-
and leptin
concentrations were measured and insulin-mediated glucose uptake and
substrate oxidation were determined by euglycemic hyperinsulinemic
glucose clamp and indirect calorimetry, respectively, in 70 healthy
subjects with a wide age range.
 |
MATERIALS AND METHODS |
Subjects and study design.
Seventy subjects (44 males and 26 females) with a wide age range
(21-94 yr) were studied. Premenopausal women were all studied in
the luteal phase. All subjects were normotensive, took no medications, were nonsmokers, and had no evidence of metabolic or cardiovascular diseases. Furthermore, erythrocyte sedimentation rate, plasma fibrinogen and lactate deydrogenase isoenzymes, hemoglobin
concentrations, and blood white cells were within normal range in all
subjects. Oral glucose tolerance (75 g glucose) (34a) was tested in all volunteers before they were enrolled, and those affected by diabetes mellitus and glucose intolerance were excluded from the study. Subjects
with a family history of NIDDM, obesity, or hypertension were also
excluded from the study. All tests were conducted in the morning and
after an overnight fast (of
12 h).
Study design consists of two parts, a cross-sectional study
(n = 70), in which associations among
all variables in the whole group of subjects were studied, and a
longitudinal study (n = 50) with a
12-mo duration. In the cross-sectional study, subjects were categorized
in relation to tertile of plasma TNF-
. Those subjects at the two
highest tertiles of plasma TNF-
were enrolled for the longitudinal
study. The reasons for such a choice were 1) to perform a longitudinal study
only in subjects in whom an association between plasma TNF-
and
whole body glucose disposal (WBGD) was already found in the
cross-sectional study and 2) to have
a reasonable number of subjects participating in the longitudinal study. At the end of the follow-up period, anthropometric
characteristics, glucose tolerance, and insulin action were
redetermined. Subjects had been on similar standard weight-maintaining
diets containing 150 g of carbohydrate per day for
7 days before all
tests.
After a clear explanation of the potential risks of the study, which
was approved by the Ethical Committee of the University of Napoli, all
volunteers provided informed consent to participate. More detailed
characteristics of the subjects are reported in Table
1.
Anthropometric determinations.
Weight and height were measured using a standard technique. Body fat
(BF) and fat- free mass (FFM) were measured using a four-terminal bioimpedance analyzer (BIA; RJL Spectrum Bioelectrical Impedance-BIA 101/SC Akern, RJL-System, Florence, Italy) (5). Prediction of FFM by
BIA was done with equations validated for a wide age range in the
elderly (5). Waist circumference was measured at the midpoint between
the lower rib margin and the iliac crest (normally umbilical level),
and hip circumference was measured at the level of trochanter. Both
circumferences were measured to the nearest 0.5 cm with a plastic tape,
and the ratio of waist to hip (WHR) was calculated.
Metabolic tests.
At baseline, blood samples for fasting plasma glucose, insulin, leptin,
free fatty acids (FFA), triglycerides, and TNF-
concentrations were
drawn. Insulin action was measured using the euglycemic
hyperinsulinemic glucose clamp technique. In this test, a priming dose
of insulin (154 pmol/kg) was given before the clamp was started. Then,
a fixed insulin infusion (Humulin R, at the rate of 7.1 pmol · kg
1 · min
1
for 120 min; Eli Lilly, Florence, Italy) and a variable amount of
glucose (as a 20% solution) were delivered. Simultaneous indirect calorimetry was performed using an open-circuit ventilated hood system
(Deltatrac Monitor, Datex, Helsinki, Finland). Respiratory quotient and
substrate oxidation rate were calculated from the oxygen consumption,
the carbon dioxide production, and the nitrogen urinary excretion rate
according to Ferrannini (10).
Analytic methods.
Plasma glucose was immediately measured by the glucose oxidase method
(Beckman Autoanalyzer; Fullerton, CA). Fasting plasma FFA
concentrations were measured in triplicate on each sample, according to
the method of Dole and Meinertz (7). Commercial enzymatic methods were
used in the determination of plasma triglyceride (Peridecrome;
Boehringer Mannheim, Milan, Italy) concentration. Blood samples for
insulin, TNF-
, and leptin measurements were stored at
80°C until the assay measurements, which were all made in
triplicate in one assay. Blood samples for insulin and TNF-
measurements were collected in heparinized tubes. After centrifugation, plasma insulin (Sorin Biomedical, Milan, Italy), leptin (Linco Research, St. Louis, MO), and TNF-
(Medgenix Diagnostic SA, Fleurus, Belgium) concentrations were determined by radioimmunoassay.
Calculations and statistical analyses.
WBGD was calculated during the final 60 min of the clamp, as previously
reported (11). In preliminary clamps, an insulin infusion rate of 7.1 pmol · kg
1 · min
1
fully suppressed (but without negative numbers) hepatic glucose output
at all ages. Nonoxidative glucose metabolism (NOGM) was calculated as
WBGD, and oxidative glucose metabolism was calculated by indirect
calorimetry (10).
For predicting the adequacy of sample size in the cross-sectional
study, an nQuery test was used. To approximate normal
distribution, plasma insulin, leptin, and triglyceride concentrations
were log transformed and used as such in all calculations. Univariate
analysis allowed us to distribute all patients in tertiles of plasma
TNF-
concentration and WBGD. The differences among each tertile were calculated by ANOVA. When ANOVA indicated a
P <0.05, Scheffé's test was
also performed. Pearson product-moment correlations were calculated to
test association among variables. Partial correlations tested the
association between two variables independent of a covariate.
Multivariate linear regression analyses tested the independent
association of each variable with plasma TNF-
concentration and
WBGD. In the longitudinal study, the relative risk (RR) estimated the
hazard of having a further decline in insulin-mediated glucose uptake
for a hypothetical subject at the 75th and 25th percentiles of the risk
factor in that subgroup, after adjustment for different covariates. For
each RR, 95% confidence intervals (CI) are presented. Statistical
analyses were performed by the SOLO (BMDP, Cork, Ireland) software
package. All values are presented as means ± SD.
 |
RESULTS |
Cross-sectional study.
In the whole group of subjects (n = 70), advancing age was significantly associated with an increase in
plasma TNF-
concentration (r = 0.64, P < 0.001) and a decline in
WBGD (r =
0.38,
P < 0.001; Fig.
1). Plasma leptin concentration was
significantly correlated with BF (r = 0.71, P < 0.001) and WHR
(r = 0.58, P < 0.001). Such correlations
persisted after adjustment for age and gender
(P < 0.008 for both). Simple
correlations between plasma TNF-
concentration and main
anthropometric and clinical variables studied are reported in Table
2. Plasma TNF-
concentration was
positively correlated with BF (Fig. 2) and
WHR, whereas no correlation with fasting plasma leptin concentration
was found. After adjustment for sex and BF, the relationship between
plasma TNF-
and age was weakened but still significant
(r = 0.31, P < 0.01), whereas
adjustment for age and sex made the relationship between plasma TNF-
and leptin concentration significant
(r = 0.29, P < 0.02; Fig.
3). In contrast, the association between
plasma TNF-
and leptin concentrations was no more significant after
adjustment for BF (r = 0.11, P < 0.18). Plasma TNF-
concentrations were also correlated with fasting plasma glucose,
insulin, triglyceride, and FFA concentrations (Table 2). Such
correlations persisted even after adjustment for age, sex, BF, and WHR.
Finally, a significant correlation between fasting plasma FFA and WBGD
(r =
0.46,
P < 0.001) was also found. In a
multivariate analysis with plasma TNF-
concentration as a dependent
variable, a model made by age, sex, BF, and WHR explained 47% of
plasma TNF-
variability. In this model, only age
(P < 0.008) and BF
(P < 0.002) were significant
determinants of plasma TNF-
concentration.

View larger version (15K):
[in this window]
[in a new window]
|
Fig. 1.
Simple correlations between age and tumor necrosis factor- (TNF- ;
r = 0.64, P < 0.001) and whole body glucose
disposal (WBGD; r = 0.38,
P < 0.001).
|
|

View larger version (19K):
[in this window]
[in a new window]
|
Fig. 3.
Partial correlation between fasting plasma TNF- and leptin
concentrations (r = 0.29, P < 0.02). All values were adjusted
for age and sex.
|
|
During insulin infusion, steady-state plasma glucose (range:
4.8-5.0 mmol/l) and insulin (range: 560-600 pmol/l)
concentrations were kept with narrow range [coefficient of
variation (CV) <4.0%] without statistically significant
differences between the sexes (P = 0.68). In these metabolic conditions, fasting plasma TNF-
concentration correlated with WBGD (r =
0.51, P < 0.001),
insulin-stimulated glucose oxidation
(r =
0.49,
P < 0.001), and NOGM
(r =
0.42, P < 0.001; Fig.
4). After control for age, sex, BF, and
WHR, plasma TNF-
was still correlated with WBGD
(r =
0.33,
P < 0.007), insulin-stimulated glucose oxidation (r =
0.28,
P < 0.02), and NOGM
(r =
0.31, P < 0.01). After control for plasma
FFA concentration, those correlations were not significant. Univariate
analysis allowed us to divide the subjects in tertiles of age- and
sex-adjusted WBGD. Subjects at the lowest tertile of WBGD also had the
most elevated plasma TNF-
concentration (91.2 ± 11.5 pg/ml)
compared with those at the 2nd (53.4 ± 10.4 pg/ml,
P < 0.01) and 3rd tertiles (24.2 ± 7.8 pg/ml, P < 0.003).
Interestingly, the correlation between WBGD and plasma TNF-
was
strong in subjects at the 1st tertile (n = 20;
r =
0.62,
P < 0.003), weak in the 2nd
(n = 28;
r =
0.42, P < 0.03), and not significant at
the 3rd (n = 22;
r =
0.31, P < 0.09) tertile of WBGD. By
univariate analysis, we divided the subjects in tertiles of fasting
plasma TNF-
concentration (1st tertile: <44.0 pg/ml; 2nd tertile:
44.0-84.0 pg/ml; 3rd tertile: >84.0 pg/ml).

View larger version (13K):
[in this window]
[in a new window]
|
Fig. 4.
Simple correlations between plasma TNF- and glucose oxidative
metabolism (GOX; r = 0.49,
P < 0.001), nonoxidative glucose
metabolism (NOGM; r = 0.42,
P < 0.001), and WBGD
(r = 0.51,
P < 0.001).
|
|
In the multivariate analysis, a model made by age, sex, BF, FFM, WHR,
and plasma TNF-
concentrations explained 69% of WBGD variability
with age (P < 0.009), BF
(P < 0.006), FFM
(P < 0.01), and TNF-
(P < 0.05) significantly and
independently associated with WBGD. Notwithstanding, this latter
association was lost after addition of FFA to the model.
Baseline plasma TNF-
samples were reassayed to test the
reproducibility of the assay. No differences in mean values (35.2 ± 3.8 vs. 34.8 ± 3.7 pg/ml, P = NS)
and in intra-assay CV (4.7 ± 0.3 vs. 4.9 ± 0.3%,
P = NS) between the first and the
control assay, respectively, were found.
Longitudinal study.
Clinical characteristics of the subjects participating to the
longitudinal study (n = 50) at
baseline and at the end of the follow-up period are reported in Table
3. At baseline, subjects had a mean age of
72.6 ± 9.3 yr, were not obese, had a prevalent central BF
distribution, and had a mean fasting TNF-
concentration of 83.4 ± 16.6 pg/ml. No subjects became diabetic or glucose intolerant. After 12 mo, no significant changes in BF content and distribution vs.
baseline values were found. Plasma TNF-
concentration at baseline
predicts a further decline in insulin-mediated glucose uptake (RR = 2.2, CI = 1.3-2.5), insulin-stimulated oxidative glucose
metabolism (RR = 1.8, CI = 1.0-2.5), and NOGM (RR = 1.6, CI = 1.0-2.8). The predictive effect of plasma TNF-
concentration on further decline in insulin-mediated glucose uptake was
found to be independent of age, sex, BF, and WHR (RR = 2.0, CI = 1.2-2.4). The predictive role of fasting plasma TNF-
concentration on insulin-mediated glucose uptake (RR = 1.2, CI = 0.8-1.5), insulin-stimulated oxidative metabolism (RR = 1.0, CI = 0.6-1.8), and NOGM (RR = 1.1, CI = 0.8-1.7) was lost after
further adjustment for fasting plasma FFA concentration.
In a subset of 29 patients of the 50 participating in the longitudinal
study, plasma TNF-
concentration was also assayed at the end of the
follow-up period. In those subjects, plasma TNF-
concentration (75.5 ± 4.8 vs. 93.7 ± 5.2 pg/ml, P < 0.03) was more elevated after the follow-up period.
 |
DISCUSSION |
Our study demonstrates that plasma TNF-
concentration is positively
associated with advancing age and negatively correlated with insulin
action and substrate oxidation. Furthermore, plasma TNF-
predicts a
further worsening of insulin-mediated glucose uptake independent of
age, sex, BF, and WHR but not of fasting plasma FFA concentrations.
Interestingly, independent of age and sex, plasma TNF-
and leptin
concentrations were also significantly correlated.
Why plasma TNF-
concentration increases with advancing age remains
to be determined. Our volunteers were healthy subjects; thus a possible
role of minor or major diseases, frequently occurring in the elderly,
should be ruled out. Most likely, plasma TNF-
concentration
parallels the age-related increase in body fatness. In our study, the
relationship between plasma TNF-
and age was assessed only by a
cross-sectional design, so a cause-effect relationship cannot be drawn.
Nevertheless, the dependency of plasma TNF-
concentration by the
age-related change in body composition can be drawn by inferred
methods. In fact, the association between age and plasma TNF-
concentration was lost after adjustment for sex and BF; furthermore, BF
was the major determinant of plasma TNF-
concentration, explaining
31% of its variability in the multivariate analysis with
anthropometric characteristics of the subjects as independent
variables.
Several factors have been suggested as contributing to age-related
impairment of glucose disposal in skeletal muscle (11, 29). Elevated
plasma TNF-
might provide a further contribution to the impairment
of glucose metabolism in the elderly. In rats, TNF-
administration
causes an increase in serum triglycerides and very low density
lipoprotein (8). TNF-
-induced hyperlipidemia is thought to be the
result of increased hepatic lipogenesis and lipolysis rather than of
decreased peripheral clearance (8). In our study, the evidence that
TNF-
may stimulate the lipolysis is strengthened by a significant
correlation between plasma TNF-
and FFA concentrations. With regard
to glucose metabolism, in vitro data showing the negative impact of
plasma TNF-
on glucose metabolism are very consistent (2, 4, 13, 18,
30, 31, 33). Briefly, obese rats treated with antibodies against the
TNF-
receptor (that is, IgG) were two to three times more sensitive
to insulin than untreated rats (27), the effect being evident at
skeletal muscle level and null at hepatic site. Furthermore, TNF-
has been shown to downregulate GLUT-4 mRNA levels in adipocytes and
myocyte cultures (4, 27). In fat cells, this effect occurs in the
context of downregulation of expression of several fat-specific genes,
such as a P2 or adipsin (27, 33), so it is not entirely specific.
Treatment of insulin-sensitive cells with TNF-
can clearly alter the
catalytic activity of the insulin receptor. In adipocytes, TNF-
treatment leads to a reduction of insulin-stimulated receptor
autophosphorylation and a more pronounced effect on insulin receptor
substrate-1 phosporylation (18). Interestingly, Groder et
al. (13) recently confirmed that TNF-
inhibits insulin receptor autophosphorylation and can act at receptor and postreceptor levels. Saghizadeh et al. (30) also demonstrated that, in muscular tissue of
insulin-resistant patients, expression of TNF-
was fourfold higher
than in subjects with normal insulin sensitivity; furthermore, an
inverse linear relationship between maximal glucose disposal rate and
degree of skeletal muscle expression of TNF-
was also observed.
Finally, Miles et al. (25) recently demonstrated that TNF-
infusion
in rats impairs insulin action, a phenomenon prevented by troglidazone
administration.
Data in vivo are contrasting. The infusion of TNF-
might impair
insulin action through a rise of counterregulatory hormone concentrations, such as glucagon, glucorticoids, and catecholamines (23). Kellerer et al. (21) demonstrated that insulin sensitivity was
not a determinant of circulating TNF-
independent of age, gender,
and percent desirable body weight in offspring of NIDDM patients. Ofei
et al. (28) did not find an improvement in insulin action with use of a
TNF-
neutralizing agent in humans. Frittitta et al. (12)
demonstrated that WBGD negatively correlated with adipose PC-1 protein
content but not with TNF-
gene expression. Our results are in
agreement with the studies showing a negative impact of plasma TNF-
on insulin sensitivity, as demonstrated by the following observations.
1) There was a negative correlation between plasma TNF-
concentration and WBGD.
2) Plasma TNF-
concentration was
an independent determinant of WBGD in multivariate analysis and
explains 21% of WBGD variability.
3) Plasma TNF-
concentration negatively correlated with insulin-stimulated oxidation and NOGM, thus
supporting the hypothesis that the cytokine deranges both receptor and
postreceptor steps of glucose metabolism.
4) In the longitudinal study, plasma
TNF-
predicts a further impairment in WBGD and substrate oxidation
independent of age, sex, BF, and WHR. Why in vivo studies are not so
consistent as in vitro studies is unknown. In our study the association
between plasma TNF-
and WBGD was absent in subjects at the 3rd
tertile of WBGD, whereas such a correlation was significant in subjects
at the 1st and 2nd tertiles of WBGD. One can hypothesize that, in vivo,
only elevated plasma TNF-
concentrations might have significant
effect on WBGD. Alternatively, one could hypothesize that TNF-
might have a local effect on the muscle that is embedded with
fat cells secreting this peptide. This does not
necessarily exclude the importance of plasma levels as an indicator for
greater local activity. Nevertheless, only studies performing a
dose-effect curve might provide a response to such possibility.
Finally, a negative impact of plasma TNF-
on insulin action might be
due to an overactivity of the glucose-fatty acid cycle. In fact, in both cross-sectional and longitudinal studies, the relationship between
TNF-
and WBGD was lost after adjustment for plasma FFA concentration.
In our study, we also observe a significant correlation between plasma
TNF-
and leptin concentration that is independent of age and sex.
Despite the fact that a correlation does not support a
pathophysiological link, our data are in agreement with other results
(9, 24) also showing a relationship between TNF-
and leptin. One can
hypothesize that BF, having a coordinate control on plasma TNF-
and
leptin concentration, might drive the relationship between these latter
two variables. The facts that plasma leptin concentration differs with
gender (16) and that plasma TNF-
concentration increases with
advancing age might provide an explication for the need to adjust for
age and sex to get a significant correlation.
In conclusion, our study demonstrates that plasma TNF-
concentration
increases with advancing age and that such an increase is associated
with an impairment in insulin-mediated glucose uptake and substrate
oxidation with advancing age.
 |
FOOTNOTES |
Address for reprint requests: G. Paolisso, Dept. of Geriatric
Medicine and Metabolic Diseases, Servizio di Astanteria Medica, Piazza
Miraglia 2, 80138 Napoli, Italy.
Received 31 December 1997; accepted in final form 24 April 1998.
 |
REFERENCES |
1.
Argiles, J. M.,
J. Lopez-Soriano,
and
F. J. Lopez-Soriano.
Cytokines and diabetes: the final step? Involvement of TNF-
in both type I and II diabetes mellitus.
Horm. Metab. Res.
26:
447-449,
1994[Medline].
2.
Ashkenazi, A.,
S. A. Marsters,
D. J. Capon,
S. M. Chamow,
I. S. Figari,
D. Pennica,
D. V. Goeddel,
M. A. Palladino,
and
D. H. Smith.
Protection against endotoxic shock by a tumor necrosis factor receptor immunoadhesin.
Proc. Natl. Acad. Sci. USA
88:
10535-10539,
1992[Abstract].
3.
Chorinchath, B. B.,
L. Y. Kong,
L. Mao,
and
R. E. McCallum.
Age-associated differences in TNF-alpha and nitric oxide production in endotoxic mice.
J. Immunol.
156:
1525-1530,
1996[Abstract].
4.
Cornelius, P.,
M. D. Lee,
M. Marlowe,
and
P. H. Pekale.
Monokine regulation of glucose transporter mRNA in L6 myotubes.
Biochem. Biophys. Res. Comm.
165:
1429-1436,
1986.
5.
Deurenberg, P.,
E. Van der Koij,
P. Evers,
and
T. Hulshof.
Assessment of body composition by bioelectrical impedance in a population aged >60 yrs.
Am. J. Clin. Nutr.
51:
3-6,
1990[Abstract].
7.
Dole, M.,
and
H. P. Meinertz.
Microdetermination of long-chain fatty acids in plasma and tissues.
J. Biol. Chem.
235:
2595-2599,
1960.
8.
Feingold, K. R., and C. Grufeld. Role of cytokines
in inducing hyperlipidemia. Diabetes
41, Suppl. 2: 97-101, 1992.
9.
Fernandez-Real, J. M.,
C. Gutierrez,
W. Ricart,
R. Casamitjana,
M. Fernandez-Castaner,
J. Vendrell,
C. Richart,
and
J. Soler.
The TNF-
gene Nco I polymorphism influences the relationship among insulin resistance, percent body fat, and increased serum leptin levels.
Diabetes
46:
1468-1472,
1997[Abstract].
10.
Ferrannini, E.
The theoretical basis of indirect calorimetry: a review.
Metabolism
37:
287-331,
1988[Medline].
11.
Ferrannini, E.,
S. Vichi,
H. Beck-Nielsen,
M. Laakso,
G. Paolisso,
and
U. Smith.
Insulin sensitivity and age.
Diabetes
45:
947-956,
1996[Abstract].
12.
Frittitta, L.,
J. F. Youngren,
P. Sbraccia,
M. D'Adamo,
A. Buongiorno,
R. Vigneri,
I. Goldfine,
and
V. Trischitta.
Increased adipose tissue PC-1 protein content, but not tumor necrosis factor
-gene expression, is associated with a reduction of both whole body insulin sensitivity and insulin receptor tyrosine kinase activity.
Diabetologia
40:
282-289,
1997[Medline].
13.
Groder, G.,
B. Bassenmeier,
M. Kellerer,
E. Copp,
B. Stoyanov,
A. Muhlhofer,
L. Berti,
H. Horisoki,
A. Ullrich,
and
H. Haring.
Tumor necrosis factor-
and hyperglycemia-induced insulin resistance. Evidence for different mechanisms and different effects on insulin signalling.
J. Clin. Invest.
97:
1471-1477,
1996[Abstract/Free Full Text].
14.
Grunfeld, C.,
C. Zhao,
J. Fuller,
A. Pollack,
A. Moser,
J. Friedman,
and
K. R. Feingold.
Endotoxin and cytokines induce expression of leptin, the ob gene product, in hamster.
J. Clin. Invest.
97:
2152-2157,
1996[Abstract/Free Full Text].
15.
Han, D.,
T. Hosokawa,
A. Aoike,
and
K. Kawai.
Age-related enhancement of tumor necrosis factor production in mice.
Mech. Ageing Dev.
84:
39-54,
1995[Medline].
16.
Havel, P. J.,
S. D. Karakas,
G. R. Dubuc,
W. Muller,
and
S. D. Phinney.
Gender differences in plasma leptin concentration.
Nature Med.
2:
949-950,
1996[Medline].
17.
Hofman, C.,
K. Lorenz,
S. S. Braithwaite,
J. R. Colca,
B. J. Polaruk,
G. S. Hotamisligil,
and
B. M. Spiegelman.
Altered gene expression for tumor necrosis factor-
and its receptor during drug and dietary modulation of insulin resistance.
Endocrinology
134:
264-270,
1994[Abstract].
18.
Hotamisligil, G. S.,
D. L. Murray,
L. N. Chay,
and
B. M. Spiegelman.
TNF-
inhibits signalling from insulin receptor.
Proc. Natl Acad. Sci. USA
91:
4854-4858,
1994[Abstract].
19.
Hotamisligil, G. S.,
and
B. M. Spiegelman.
Tumor necrosis factor-
: a key component of the obesity-diabetes link.
Diabetes
43:
1271-1278,
1994[Abstract].
20.
Kawadami, M.,
P. H. Pekala,
M. D. Lone,
and
A. Cerami.
Lipoprotein lipase suppression in 3T3-L1 cells by an endotoxin-induced mediator from exudate cells.
Proc. Natl. Acad. Sci. USA
82:
912-916,
1982.
21.
Kellerer, M.,
K. Rett,
W. Renn,
L. Groop,
and
H. U. Haring.
Circulating TNF-alpha and leptin levels in offsprings of NIDDM patients do not correlate to individual insulin sensivity.
Horm. Metab. Res.
28:
737-743,
1996[Medline].
22.
Kennedy, A.,
T. W. Gettys,
P. Watson,
P. Wallace,
E. Ganaway,
Q. Pan,
and
W. T. Garvey.
The metabolic significance of leptin in humans: gender-based differences in relationship to adiposity, insulin sensitivity and energy expenditure.
J. Clin. Endocrinol. Metab.
82:
1293-1300,
1996[Abstract/Free Full Text].
23.
Lang, C. H.,
C. Dobresen,
and
G. J. Bagby.
Tumor necrosis factor impairs insulin action on peripheral glucose disposal and hepatic glucose output.
Endocrinology
130:
43-52,
1992[Abstract].
24.
Mantzoros, C.,
S. Moschos,
I. Avramopoulos,
V. Kaklamani,
A. Liolios,
D. E. Doulgerakis,
I. Griveas,
N. Katsilambros,
and
J. S. Flier.
Leptin concentration in relation to body mass index and the tumor necrosis factor-
system in humans.
J. Clin. Endocrinol. Metab.
82:
3408-3414,
1997[Abstract/Free Full Text].
25.
Miles, P. D. G.,
O. M. Romeo,
K. Higo,
A. Cohen,
K. Rafaat,
and
J. M. Olefsky.
TNF-
induced insulin resistance in vivo and its prevention by troglidazone.
Diabetes
46:
1678-1683,
1997[Abstract].
26.
Morin, C. L.,
M. J. Pagliasotti,
D. Windmiller,
and
R. H. Eckel.
Adipose tissue-derived tumor necrosis factor-alpha is elevated in older rats.
J. Gerontol.
52:
B190-B195,
1997.
27.
Norman, R. A.,
C. Bogardus,
and
E. Ravussin.
Linkage between obesity and a marker near the tumor necrosis factor-
locus in Pima Indians.
J. Clin. Invest.
96:
158-162,
1995[Medline].
28.
Ofei, F.,
S. Hurel,
J. Newkirk,
M. Sopwith,
and
R. Taylor.
Effect of engineered human anti-TNF-alpha antibody (CDP571) on insulin sensitivity and glycemic control in patients with NIDDM.
Diabetes
45:
881-885,
1996[Abstract].
29.
Paolisso, G.,
A. S. Scheen,
and
P. J. Lefebvre.
Glucose handling, diabetes and ageing.
Horm. Res.
43:
52-57,
1995[Medline].
30.
Saghizadeh, M.,
J. M. Ong,
W. T. Garvey,
R. R. Henry,
and
P. A. Kern.
The expression of TNF-
by human muscle: relationship to insulin resistance.
J. Clin. Invest.
97:
1111-1116,
1996[Abstract/Free Full Text].
31.
Sakuri, Y.,
X. J. Zhang,
and
R. Wolff.
Short term effects of tumor necrosis factor and energy and substrate metabolism in dog.
J. Clin. Invest.
91:
2437-2445,
1993[Medline].
32.
Spiegelman, B. M.,
and
G. S. Hotamisligil.
Through thick and thin: wasting obesity and TNF-
cells.
Cell
73:
625-627,
1993[Medline].
33.
Stephens, J. M.,
and
P. H. Pekale.
Transcriptional repression of the Glut4 and C/EBP genes in 3T3-L1 adipocytes by tumpor necrosis factor-
.
J. Biol. Chem.
266:
21839-21845,
1991[Abstract/Free Full Text].
34.
Torti, F. M.,
B. Dieckman,
A. Beutler,
A. Cerami,
and
G. M. Reingold.
A macrophage factor inhibits adipocyte gene expression: an in vitro model of cachexia.
Science
229:
867-869,
1985[Medline].
34a.
World Health Organization.
Diabetes Mellitus: Report of a WHO Study Group. Geneva: WHO, 1995, p. 9-17. (Tech. Rep. Ser. 727)
35.
Zhang, Y.,
R. Proenca,
M. Maffei,
M. Barone,
L. Leopold,
and
J. M. Friedman.
Positional cloning of the mouse obese gene and its human homologue.
Nature
372:
425-432,
1994[Medline].
Am J Physiol Endocrinol Metab 275(2):E294-E299
0002-9513/98 $5.00
Copyright © 1998 the American Physiological Society