1 Departments of Reproductive Biology and 2 Nutrition, Case Western Reserve University School of Medicine at MetroHealth Medical Center, Cleveland, Ohio 44109; 3 Noll Physiological Research Center, Pennsylvania State University, University Park, Pennsylvania 16802; and 4 Nutrition, Metabolism, and Exercise Division, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72114
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ABSTRACT |
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Changes in tumor necrosis
factor- (TNF-
) may provide a mechanism to explain impaired
glucose metabolism with advancing age. Hyperglycemic clamps (180 min,
10 mM) were performed on seven older [67 ± 2 yr; body mass index
(BMI) 24.7 ± 1.0 kg/m2] and seven younger (22 ± 1 yr; BMI 21.8 ± 1.3 kg/m2) healthy sedentary
males with normal glucose tolerance. TNF-
production at basal and at
the end of 180 min of hyperglycemia and hyperinsulinemia was measured
ex vivo from lipopolysaccharide-stimulated (1 ng/ml) peripheral blood
mononuclear cells. Plasma glucose, insulin, and C-peptide levels were
similar in both groups at basal and during the last 30 min of the
hyperglycemic clamp. Glucose infusion rates were lower
(P < 0.004) in the older group compared with the
young, indicating decreased insulin action among the older subjects.
Basal TNF-
secretion was similar in older and younger subjects.
TNF-
was suppressed (P < 0.02) in the younger group
(230 ± 46 vs. 126 ± 49 pg/ml; basal vs. clamp) but not in the older group (153 ± 37 vs. 182 ± 42 pg/ml), with
significant group differences in response (P < 0.05).
A significant correlation was observed between the level of suppression
in TNF-
production and insulin action (Kendall's rank,
= 0.40, P < 0.05). Furthermore, the TNF-
response
during the clamp was related to fat mass (r = 0.88, P < 0.001) and abdominal fat (r = 0.81, P < 0.003). In conclusion, these findings
suggest a possible mechanism by which TNF-
may modulate glucose
metabolism in younger people. Aging and modest increases in adiposity
prevent the "normal" suppression of TNF-
production after a
sustained postprandial-like hyperglycemic-hyperinsulinemic stimulus,
which may contribute in part to the decline in insulin sensitivity in
older men.
insulin resistance; obesity; diabetes; abdominal adiposity
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INTRODUCTION |
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HUMAN AGING is
associated with the development of glucose intolerance
(2), abnormal pancreatic -cell secretion (3, 18,
25, 32), and insulin resistance (6, 8, 26). However, it is unclear as to the mechanism responsible for these changes as people age. Recent investigations have implicated the cytokine tumor necrosis factor (TNF)-
as a modulator of glucose metabolism. Particularly, TNF-
has been associated with the
metabolic defects related to insulin resistance. In vitro
studies show that TNF-
can induce insulin resistance and
downregulate insulin receptor signaling in cultured adipocytes
(22), hepatocytes (14), and skeletal muscle
(10). Furthermore, increased TNF-
is associated with
insulin resistance in obesity (23), sepsis
(29), after muscle damage (11), and with
age-associated muscle wasting (17). Interestingly,
elevated plasma TNF-
levels have been observed in older men and
women (37), and increased TNF-
protein expression has
been reported in adipose tissue and skeletal muscle of obese and
diabetic humans (24, 35, 40). Indeed, TNF-
may provide a link to explain the impaired glucose metabolism that is seen with
advancing age. Furthermore, the normal age-related increases in body
fat and abdominal adiposity (41) may be related to the effects of age on TNF-
and its role as a glucoregulatory modulator.
The purpose of this investigation was to determine the effects of
physiologically elevated levels of glucose and insulin on TNF-
production in healthy sedentary older men. To determine the effects of
age on TNF-
production, the responses among these older men were
compared with those of a group of healthy sedentary younger men.
Because the focus of the investigation was to examine underlying
abnormalities in TNF-
and glucoregulation among successfully aging
older adults, the older and younger men had normal glucose tolerance
and pancreatic
-cell secretion and were not obese.
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METHODS |
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Subjects. Fourteen men (7 younger, age 21-28 yr, and 7 older, age 59-75 yr) participated in this study. All subjects were screened for acute and chronic diseases, and none was taking medications that would affect carbohydrate metabolism or immune function. In addition, all of the subjects were sedentary, with a similar activity level between groups, as assessed by a physical activity questionnaire. None of the subjects was involved in any regular exercise regimen for at least 6 mo before the time of testing. All participants had a normal plasma glucose response to a 75-g oral glucose tolerance test (1). All of the subjects provided written informed consent in accordance with The Pennsylvania State University guidelines for the protection of human subjects.
Height without shoes was measured to the nearest 1.0 cm. Body weight was measured to the nearest 0.1 kg. Body circumferences were measured at the waist (level of the umbilicus) and hip (point of widest circumference around the buttocks). Waist circumference and waist-to-hip ratio were used to estimate abdominal adiposity (26). Body density and body fat were determined by hydrostatic weighing after an overnight fast as previously described (28).Study design. All of the trials included residence at the General Clinical Research Center (GCRC) for three nights and two consecutive days (day 1 and day 2). Subjects consumed a balanced diet and received all of their meals from the GCRC for the 2 days before the clamp (young, 3,704 ± 94 kcal; old, 2,613 ± 130 kcal). During these 2 days, the subjects maintained a normal level of activity and did not exercise. Hyperglycemic clamps were performed on day 3 of residence.
Hyperglycemic clamp. The hyperglycemic clamp (180 min, 10.0 mM) was performed as described by DeFronzo et al. (9). After an overnight fast (~12 h), the subjects voided morning urine and were weighed. An 18-gauge polyethylene catheter was inserted in an antecubital vein for the infusion of glucose (20% dextrose). A second 20-gauge polyethylene catheter was inserted in retrograde fashion in a dorsal hand vein, and the hand was warmed in a heated box (~65°C) for sampling of arterialized venous blood. Baseline blood samples were drawn for glucose, insulin, and C-peptide determination. Subsequently, plasma glucose concentrations were raised to 10.0 mM within 15 min by using a primed glucose infusion with a variable-speed infusion pump (Harvard Apparatus, South Natick, MA). Plasma glucose concentrations were maintained at 10.0 mM for a further 165 min by a variable-rate infusion based on the prevailing plasma glucose concentration. Blood samples (0.5 ml) were drawn every 5 min and were assayed immediately by the glucose oxidase method (Beckman Instruments, Fullerton, CA). The glucose concentrations were used to adjust the infusion rate throughout the clamp procedure. In addition, blood samples (3.0 ml) were drawn every 2 min for the first 10 min (0-10 min) and every 15 min for the remainder of the clamp procedure (15-180 min) to determine insulin and C-peptide concentrations during the first (0-10 min) and second (10-180 min) phases of pancreatic secretion. At the conclusion of the clamp, a urine sample was obtained for the determination of glucose concentration.
Analytical methods.
Mononuclear cell (MNC) isolation and culture were performed on 20 ml of
arterialized venous blood, which was obtained at 0 and 180 min of the
clamp. The cells were isolated by Ficoll-Hypaque centrifugation
(4), washed two times in pyrogen-free saline, suspended in
RPMI (100 U/ml penicillin, 100 µg/ml streptomycin, and 0.3 mg/ml
L-glutamine) with serum substitute TCH, and seeded in
coated culture plates (2.5 × 106 cells/ml).
The cells were then incubated (humidified, 5% CO2, 37°C)
for 24 h with lipopolysaccharide endotoxin (LPS, 1 ng/ml). After
incubation, supernatants (10,000 g for 1 min) were obtained and stored at 70°C until analysis. TNF-
concentrations were measured in duplicate by ELISA (Endogen, Woburn, MA). Complete blood
counts were obtained using a Coulter Counter (Coulter Instruments). Plasma insulin and C-peptide concentrations were determined in duplicate by double-antibody RIA using commercial kits (Linco Research,
St. Charles, MO, and Diagnostic Products, Los Angeles, CA). To reduce
interassay variability, all samples for each subject were run in the
same assay.
Statistics.
The MIXED procedure for the Statistical Analysis System (SAS Institute,
Cary, NC) was used for ANOVA by the rank transformation (nonparametric)
approach to identify statistical differences in the data. Primary
dependent variables were analyzed by two-way repeated-measures ANOVA
with the following main effects: group (young and old) and trial (basal
and clamp). Descriptive data were analyzed using a one-way ANOVA.
Model-adjusted P values from a comparison of the
least-squared means were used to determine differences between basal
and clamp within groups. Group-by-trial interaction was used to
demonstrate group differences in measured responses when the basal was
compared with the clamp within groups. Spearman product-moment
correlations were used to determine the relationship between the
TNF- response and body composition. Kendall's rank,
, was used
to determine the relationship between the change in TNF-
production
and estimated insulin action. All values are expressed as means ± SE. An
-level of 0.05 was used to determine statistical significance.
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RESULTS |
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Subjects were similar in weight, fat-free mass, and body mass
index (BMI), but the older group had a higher fat mass, waist circumference, and waist-to-hip ratio (Table
1). All subjects had a normal response to
an oral glucose tolerance test (2-h value, 5.6 ± 0.4 mM for the
older group and 5.7 ± 0.5 mM for the younger group). Basal
glucose, insulin, and C-peptide levels were within normal limits and
were similar between the two age groups (Table 2). Both groups were clamped at similar
glucose levels, and there was no difference in the insulin and
C-peptide response to hyperglycemia (Table 2). However, the glucose
infusion rate that was required to maintain hyperglycemia in the older
group was less than the rate in the younger group (10.0 ± 0.1 vs.
6.7 ± 0.6 mg · kg fat-free mass1 · min
1, P < 0.004). To estimate insulin action in the two groups, the glucose
disposal rate (M value, calculated from the glucose infusion rate from
150 to 180 min and adjusted for the glucose equivalent space and
urinary glucose loss, if any) was divided by the corresponding insulin
concentration (I). Insulin action was reduced (P < 0.02) in the older men (Fig. 1).
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TNF- production was similar for both groups in the basal state.
However, hyperglycemia and hyperinsulinemia resulted in a suppression
of TNF-
secretion in the young subjects but no change in the older
men (Table 2 and Fig. 2). The response
between the two groups was significantly different (P < 0.05). Univariate analysis revealed a direct relationship between
TNF-
production after hyperglycemia-hyperinsulinemia and both
fat mass (r = 0.88, P < 0.001) and
waist circumference (r = 0.81, P < 0.003) for the combined groups (Figs. 3
and 4). In addition, the amount of
suppression in TNF-
production during hyperglycemia-hyperinsulinemia
was directly associated with insulin action, estimated from the M-to-I ratio during the clamp (Kendall's rank,
= 0.40, P < 0.05). As shown in Table 2, plasma TNF-
concentrations followed similar trends as monocyte TNF-
production
in both groups; however, the decrease after
hyperglycemia-hyperinsulinemia for the young was not significant
(P = 0.20). Basal plasma TNF-
concentrations were
not significantly increased in the older compared with younger men
(P = 0.18).
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Total MNC, lymphocyte, monocyte, and granulocyte numbers were similar
for both the older and younger groups under basal conditions (Table
3). The hyperglycemic-hyperinsulinemic
conditions that prevailed during the clamp resulted in a significant
decrease in total MNC and lymphocyte numbers in both groups. Monocyte
number was decreased in the older group but not the young. Granulocyte number was not changed in either group.
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DISCUSSION |
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The present study is the first to show that, although older
healthy men may have normal glucose tolerance, there is an underlying abnormality in TNF- production when presented with a sustained physiological hyperglycemic and hyperinsulinemic challenge.
Compared with a group of healthy young men, the older men failed
to show a "normal" suppression in TNF-
production under
postprandial-like conditions. Our data provide further support for the
role of TNF-
as a modulator of insulin-mediated glucose metabolism,
and, indeed, TNF-
may contribute to the decline in insulin action
observed among these older men. Although the older men were relatively lean, fat mass and abdominal fat were significantly greater than in the
young group. Furthermore, the independent associations between TNF-
and both fat mass and waist circumference suggest that the increased
body fat, particularly abdominal fat, may be a key determinant of the
observed differences in TNF-
secretion and its potential role in
modulating insulin action.
The effect of in vivo hyperglycemia, or simultaneous hyperglycemia and
hyperinsulinemia, on TNF- secretion in humans remains unknown,
despite the fact that these conditions are most reflective of the
postprandial state and may have a considerable bearing on the
development of insulin resistance. Indeed, much of what we know about
the relationship between TNF-
and glucose metabolism is based on
studies that have examined how TNF-
affects insulin receptor
signaling and consequently glucose uptake or how TNF-
stimulates
insulin secretion from
-cells (19, 20, 36). In vitro
studies using supraphysiological glucose concentrations (>22 mM) have
reported an increase in TNF-
secretion from healthy human peripheral
blood MNCs (20, 36). The exact mechanism by which
hyperglycemia alters TNF-
secretion in these cells is unknown, but
hyperglycemia can stimulate transcription of TNF-
mRNA and protein
turnover, with a possible mechanism being the increased osmolarity that
is associated with high glucose (36).
In contrast to these in vitro studies with hyperglycemia, healthy
sedentary young men in the present study showed an ~45% decrease in
TNF- secretion after hyperglycemia and hyperinsulinemia. We took
these data to represent the normal in vivo TNF-
response to 3 h
of hyperglycemia coupled with hyperinsulinemia in males. So, is there a
physiological benefit to decreased TNF-
secretion after
hyperglycemia and hyperinsulinemia in these young men? It is now well
documented that TNF-
can impair insulin receptor signaling in
adipose tissue and skeletal muscle, thereby decreasing insulin-mediated
glucose uptake (10, 11, 14, 22, 23, 29). It was recently
shown that TNF-
promotes Ser307 phosphorylation of
insulin receptor substrate (IRS)-1, which impairs IRS-1 association
with the insulin receptor, thus inhibiting downstream insulin signaling
(39). Furthermore, TNF-
production by monocytes from
healthy young men is positively correlated with the activity of the
downstream protein phosphatidylinositol 3-kinase in skeletal muscle
during transient insulin resistance (11). Because TNF-
appears to play an important role in reducing insulin-stimulated glucose metabolism, it may be beneficial to be able to control TNF-
production when there is a need to increase glucose disposal. The
decrease in TNF-
secretion among the younger group suggests a novel
mechanism whereby TNF-
suppression may help to modulate and
facilitate glucose disposal.
In contrast, healthy sedentary older men failed to suppress TNF-
secretion during similar hyperglycemic and hyperinsulinemic conditions.
Furthermore, even though the older men had normal glucose tolerance and
a similar insulin secretion as the younger subjects, glucose infusion
rates were lower in the older group. The glucose infusion rates were
calculated relative to the prevailing insulin concentration (M-to-I
ratio) and were used as a surrogate measure of insulin resistance. As
shown previously (13, 25, 28), insulin resistance was
increased among the older group. The correlation between the degree of
TNF-
suppression and insulin action suggests that the mechanism
responsible for impaired glucose metabolism in the older men may be
related to TNF-
. It has been shown that plasma TNF-
is increased
with advancing age, and the increase is associated with insulin
resistance (37). A similar observation has been reported
when comparing plasma TNF-
levels in young and old rats
(33). Furthermore, when old rats are infused with TNF-
,
they experience increased insulin resistance (33). When
these observations are coupled with TNF-
production data from the
present study, the emerging hypothesis is that the decline in insulin
sensitivity with advancing age may be related to impaired suppression
of TNF-
secretion, particularly during postprandial periods when
glucose and insulin levels are elevated.
The effect of aging per se on TNF- secretion under basal conditions
has not been clearly established (38). In the present study, data collected before the clamp allowed us to compare TNF-
production in older vs. younger men. Although TNF-
secretion was
~33% lower in the older compared with the younger group, the difference was not significant. Mooradian et al. (34) also
reported ~40% lower TNF-
secretion when comparing young men with
an older group of subjects, which again was not significantly
different. Roubenoff et al. (38) found that LPS-stimulated
TNF-
secretion was not increased with age. In contrast, several
studies report a decrease in LPS-induced TNF-
production with age
(5, 12, 16). The similarity in the TNF-
response
between the young and old groups under fasting conditions in the
present study, and the difference between these results and the
findings of other investigators who have shown a decrease in TNF-
secretion with age, may be a function of the relative health status of
the study subjects. The older subjects in our study were very healthy,
took no medications, and had no acute or chronic cardiovascular or metabolic abnormalities. They were in the healthy category according to
NHANES III data, were not overweight, and had a BMI of <25 kg/m2. Approximately 30% of 65- to 74-yr-old men in the
United States have a BMI <25 kg/m2 (27). We
also controlled for the activity level before the procedures and
standardized the diet and residence before testing. Thus these data are
relevant to healthy aging per se and are not influenced by age-related
diseases or antecedent diet and physical activity.
The change in TNF- secretion after hyperglycemia and
hyperinsulinemia was directly related to fat mass and abdominal fat. Although both groups of men were relatively lean, the older men did
have greater fat mass and waist circumference compared with the younger
group. Thus it appears that, with advancing age, even modest increases
in adiposity, especially in the abdominal region, may contribute to the
inability to suppress TNF-
secretion during hyperglycemia and
hyperinsulinemia. These data extend our previous observations
(25, 26) and those of Coon et al. (7) showing that age-related changes in insulin resistance were a function of
abdominal adiposity. The present data are particularly interesting because they provide a potential mechanism to explain these
observations and are supported by earlier reports linking obesity,
elevated TNF-
expression, and insulin resistance (21, 23, 24,
40). The issue of body fat distribution is particularly
important in light of a recent report that TNF-
secretion from
subcutaneous adipose tissue of obese women is related to
insulin-stimulated glucose transport in adipocytes (30).
Data from the present study suggest that abdominal adiposity is also
associated with altered TNF-
secretion from monocytes in nonobese
older men who have experienced an age-related increase in insulin
resistance. Additional studies will be required to determine whether
being overweight or obese increases or decreases TNF-
further and
whether these changes are associated with glucose metabolism.
Fasting MNC numbers were similar in older and younger men and were
suppressed to the same extent in both groups after the clamp. Monocytes
were reduced in older, but not younger, men after the clamp. The reason
for the decrease in the older men is unclear, but it is known that
hyperglycemia can induce monocyte adherence to endothelium in diabetic
rats through an increase in nonenzymatic glycation adducts
(15). It is also known that there is an increased accumulation of advanced glycation end products (AGE) with advancing age, particularly in the presence of diabetes (31, 42).
Although we did not measure AGEs in the present study, it is quite
likely that there was greater accumulation in the older men, which
would in turn facilitate greater adherence of monocytes in response to
hyperglycemia and hyperinsulinemia compared with the younger group.
Because the binding of AGEs to monocytes initiates cytokine-mediated processes (31), it is also possible that this mechanism
may help to explain the different TNF- response between the young and old groups. It is important to note that, despite differences between pre- and postclamp whole blood monocyte number, the in vitro
component of the study allowed us to evaluate TNF-
secretion from
equal numbers of monocytes in each group.
In conclusion, we observed an age-related impairment in TNF-
production during hyperglycemia and hyperinsulinemia. The failure to
suppress TNF-
secretion among healthy older individuals compared with a younger group represents a unique observation in light of the
decline in insulin action with age. Moreover, the association between
TNF-
production and both total and abdominal fat suggests that
modest increases in adiposity may be responsible for the different
TNF-
responses in our groups. Thus the present data add to the
growing body of literature drawing relationships between aging, glucose
intolerance, changes in body composition, and modulatory factors such
as TNF-
. These data raise the intriguing possibility that, during
postprandial periods when glucose and insulin are elevated, TNF-
production is decreased to facilitate glucose uptake by
insulin-sensitive tissues. The loss of this postprandial response may
be one of the factors contributing to insulin resistance with advancing age.
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ACKNOWLEDGEMENTS |
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We thank the nursing/dietary staff of the General Clinical Research Center and the technical/engineering staff of the Noll Physiological Research Center for supporting the implementation of the study and assisting with data collection. We also thank David Williamson, Donal O'Gorman, Christiana Lakatta, Jazmir Hernandez, Chris Marchetti, and Cormac Ryan for assistance. We are grateful to Allen R. Kunselman at the Center for Biostatistics and Epidemiology at the Hershey Medical Center for assistance in data analysis and interpretation.
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FOOTNOTES |
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This research was supported by National Institutes of Health Grants AG-12834 to J. P. Kirwan, AG-11811 to W. J. Evans, and MO1 RR-10732.
Address for reprint requests and other correspondence: J. P. Kirwan, Case Western Reserve Univ. School of Medicine at MetroHealth Medical Center, Depts. of Reproductive Biology & Nutrition, Bell Greve Bldg., Rm G-232E, 2500 MetroHealth Dr., Cleveland, OH 44109-1998 (E-mail: jkirwan{at}metrohealth.org).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 28 June 2001; accepted in final form 1 August 2001.
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