Noll Physiological Research Center and the General Clinical Research Center, The Pennsylvania State University, University Park, Pennsylvania 16802
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ABSTRACT |
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Eccentric exercise
(ECC) causes muscle damage, insulin resistance, and increased
pancreatic -cell secretion in young individuals. However, the
effects of age on the pancreatic
-cell response to glucose after ECC
are unknown. Hyperglycemic clamps (180 min, 10.0 mM) were performed on
eight young (age 22 ± 1 yr) and eight older (age 66 ± 2 yr)
healthy sedentary males without exercise (CONT) and 48 h after ECC. ECC
increased (P < 0.02) muscle soreness ratings and plasma creatine kinase concentrations in both groups. Insulin and C-peptide secretions were similar between young and older
subjects during CONT clamps. ECC increased
(P < 0.05) first-phase (0-10
min) C-peptide area under the curve in young (4.2 ± 0.4 vs. 3.7 ± 0.6 nM · min; ECC vs. CONT,
respectively) but not in older subjects (3.2 ± 0.7 vs.
3.5 ± 0.7 nM · min; ECC vs. CONT), with
significant group differences (P < 0.02). Indeed, ECC repressed (P < 0.05) first-phase peak C-peptide concentrations in older subjects (0.93 ± 0.16 vs. 1.12 ± 0.11 nM; ECC vs. CONT). Moreover, first-phase
C-peptide-to-insulin molar ratios suggest age-related differences
(P < 0.05) in insulin/C-peptide
clearance after ECC. Furthermore, the observed C-peptide response after
ECC was related to abdominal adiposity
[r =
0.62,
P < 0.02, and
r =
0.66,
P < 0.006, for first and second
(10-180 min) phases, respectively]. In conclusion, older
individuals did not exhibit the compensatory increase in
-cell
secretion observed among young individuals after ECC. Thus, with
increasing age, the pancreatic
-cell may be less responsive to the
physiological stress associated with ECC.
hyperglycemic clamp; C-peptide; insulin; exercise-induced muscle damage; abdominal adiposity
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INTRODUCTION |
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HUMAN AGING IS ASSOCIATED with the development of
glucose intolerance (24), insulin resistance (8, 23), and abnormal pancreatic -cell secretion (5, 11, 14, 32). A decline in physical
activity and changes in body composition with advancing age may
contribute to the deterioration of glucose metabolism (25). It has been
suggested that a combination of
-cell dysfunction and insulin
resistance in older individuals may lead to the eventual onset of
impaired glucose tolerance (IGT) (33) and type 2 diabetes (41).
However, the relative contributions of pancreatic
-cell secretion
and insulin action to the disturbances in glucose metabolism with aging
are not clear. In contrast, some individuals maintain normal glucose
tolerance and
-cell secretion as they age. It is unknown whether
this subset of the older population sustains a normal pancreatic
-cell response to glucose under conditions of physiological stress.
Recently, acute and chronic exercise has been used as a physiological
stressor to examine pancreatic -cell responsivity and insulin action
among the older population. Chronic exercise training studies have
shown reduced
-cell secretion and enhanced insulin action in older
individuals (23), comparable to what has been shown previously in young
individuals (19). In contrast, an acute bout of exercise with a
predominance of eccentric (muscle fiber lengthening) rather than
concentric (muscle fiber shortening) contractions (2) has been shown to
induce transient insulin resistance (3, 22) and increase the pancreatic
-cell response to glucose (20, 21) in young individuals. Eccentric
exercise results in myofibrillar damage (12), muscle soreness (17), and
elevated plasma myocellular protein levels (31). The metabolic consequences of exercise-induced muscle damage have not been determined among the older population, particularly with regard to the response of
the pancreatic
-cell.
The purpose of this investigation was to determine whether the
physiological stress associated with eccentric exercise alters the
pancreatic -cell response to hyperglycemia in healthy sedentary older individuals. The effects of age on pancreatic
-cell function were determined by comparing the
-cell response to hyperglycemia after eccentric exercise for the older individuals with the response among a group of healthy sedentary young individuals.
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METHODS |
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Subjects.
Eight young (age 21-28 yr) and eight older (age 59-75 yr)
male volunteers provided informed consent in accordance with The Pennsylvania State University guidelines for the protection of human
subjects. All of the subjects were healthy and were not diagnosed for
any acute/chronic disease or using any medications. 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 6 mo before
the time of testing. All participants had a normal plasma glucose
response to a 75-g oral glucose tolerance test (30) and did not have a
family history of diabetes mellitus.
Study design. All of the subjects participated in two trials (at least 1 wk apart). Both trials included residence at the General Clinical Research Center (GCRC) for 3 nights and 2 consecutive days (day 1 and day 2). A specific research diet was provided for 2 days, and activity level was kept to a minimum. On day 1, the subjects performed either no exercise (CONT) or one session of eccentric resistance exercise (ECC). Hyperglycemic clamps were performed on day 3 (48 h postexercise) for both CONT and ECC trials.
Exercise. The subjects performed 10 sets of 10 repetitions of leg extension (right and left legs, separately) and chest press exercises using Universal weight machines (Universal Gym Equipment, Cedar Rapids, IA). The resistance was initially set at 100% of predetermined strength (3-repetition maximum; both concentric and eccentric phases). The subject received the weight at full extension of either of the legs (right and left legs, separately) or the arms and lowered the weight in a steady fashion through the full range of motion, with ~3 s for each repetition. When the time of contraction fell below ~3 s, the resistance was reduced by 2.3 and 4.5 kg for the leg extension and chest press, respectively. Measurements of muscle soreness in the upper body and lower body were obtained at 24 and 36 h after exercise, as described previously by Edwards et al. (10). Ratings of perceived soreness were obtained while a constant 40 N (4.1 kg) of pressure was applied to test sites using a spring-loaded pressure applicator with a 2-cm-diameter probe end. The scale for determination of perceived soreness ranged from 0 ("absence of soreness") up to 9 ("unbearable soreness") arbitrary units. Plasma creatine kinase (CK) concentrations were measured 48 h after both CONT and ECC on the morning of the clamp procedure.
Diet. All subjects consumed at least 250 g of carbohydrate for 3 days preceding each trial. During day 1 and day 2 of residence, the subjects consumed a eucaloric diet (60% carbohydrate, 25% fat, 15% protein). A similar diet was consumed during the CONT and ECC trials. Total calories were calculated using the Harris-Benedict equation (15).
Hyperglycemic clamp.
Hyperglycemic clamps (180 min, 10.0 mM) were 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 into an antecubital vein for the infusion of
glucose (20% dextrose). A second 20-gauge polyethylene catheter was
inserted in retrograde fashion into a dorsal hand vein, and the hand
was warmed in a heated box (~65°C) for sampling of arterialized
venous blood (27). Baseline blood samples were drawn for plasma
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, Millis, MA). Plasma glucose concentrations were maintained
at 10.0 mM for another 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 plasma was immediately assayed 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
plasma insulin and C-peptide concentrations during the first (0-10
min) and second (10-180 min) phases of -cell secretion. At the
conclusion of the clamp, a urine sample was obtained for the
determination of glucose concentration.
Analytic methods. Plasma insulin and C-peptide concentrations were determined in duplicate by double-antibody RIA (29) with the use of commercial kits (for insulin: Linco Research, St. Charles, MO; for C-peptide: Diagnostic Products, Los Angeles, CA). To reduce interassay variability, all samples for each subject were run in the same assay. Plasma CK concentrations were measured in duplicate using a quantitative colorimetric procedure (Sigma procedure no. 520; Sigma Diagnostics, St. Louis, MO).
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. Group differences in the descriptive data were determined using a one-way ANOVA. Primary dependent variables were analyzed by a two-way repeated-measures ANOVA, with the main effects being group (young and older) and trial (CONT and ECC). Model-adjusted P values from a comparison of the least squared means were used to determine differences between ECC and CONT within groups. Group-by-trial interaction was used to demonstrate group differences in the measured responses when ECC was compared with CONT within groups. In addition, Spearman product-moment correlations were used to determine the relationship between C-peptide response and body composition. All values are expressed as means ± SE. An alpha level of 0.05 was used to determine statistical significance.
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RESULTS |
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Subjects.
Physical characteristics are summarized in Table
1. Body weight, body mass index, and
fat-free mass (FFM) were similar among subjects. However, percent body
fat, fat mass, and WHR were higher (P < 0.04) in the older subjects.
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Exercise.
All subjects performed 10 sets of 10 repetitions of leg extension and
chest press exercises at an initial resistance of 100% of
predetermined strength (3-repetition maximum). Both groups experienced
a similar rate of decline in resistance over the 10 sets. Young
subjects lifted 34.7 ± 1.9, 33.0 ± 1.8, and 51.1 ± 7.1 kg
for the right leg, left leg, and chest exercises, respectively, with
reduced resistances (%/10 sets) of 4.5 (P < 0.01),
1.8 (not significant; NS), and
16.0(P < 0.01), respectively. Older subjects lifted 24.1 ± 2.6, 23.9 ± 2.4, and 35.8 ± 4.5 kg for the right leg, left leg, and chest
exercises, respectively, with reduced resistances (%/10 sets) of
4.6 (P < 0.01),
1.3 (NS), and
13.4
(P < 0.01), respectively. Muscle soreness ratings for the
upper body and lower body were elevated
(P < 0.005) at 24 and 36 h after
exercise compared with preexercise in all subjects, with no age
group differences. Peak soreness at 36 h was exhibited in the triceps
(7.1 ± 0.8 and 5.6 ± 0.8 units for young and older subjects,
respectively), pectorals (6.3 ± 0.7 and 5.5 ± 0.6 units for
young and older subjects), and quadriceps (4.3 ± 0.9 and 3.9 ± 0.6 units for young and older subjects). Plasma CK concentrations were
elevated (P < 0.02) on the morning
of the ECC clamp compared with CONT trial in both young (1,179 ± 480 vs. 58 ± 17 IU/l; ECC vs. CONT, respectively) and older
subjects (629 ± 418 vs. 49 ± 15 IU/l; ECC vs. CONT), with no
age group differences.
Basal glucose, insulin, and C-peptide. Fasting glucose, insulin, and C-peptide concentrations were similar on the morning of the clamp in both the young (5.1 ± 0.1 vs. 5.1 ± 0.1 mM, 52 ± 3 vs. 52 ± 2 pM, and 0.38 ± 0.07 vs. 0.34 ± 0.08 nM for glucose, insulin, and C-peptide, respectively; ECC vs. CONT) and older subjects (5.3 ± 0.1 vs. 5.3 ± 0.1 mM, 56 ± 4 vs. 57 ± 4 pM, and 0.39 ± 0.08 vs. 0.42 ± 0.10 nM for glucose, insulin, and C-peptide, respectively; ECC vs. CONT).
Insulin and C-peptide.
Insulin and C-peptide responses to glucose were determined for the
first (0-10 min) and second (10-180 min) phases of -cell secretion by the calculated area under the curve (AUC) with the use of
a trapezoidal model. No differences were observed for either insulin or
C-peptide AUC when older subjects were compared with young subjects
during CONT clamps for either the first or second phase.
However, the first-phase C-peptide AUC (Table
2) was increased (P < 0.05) after ECC compared with
CONT in the young subjects but not among older subjects. Moreover, the
first-phase C-peptide AUC response when ECC was compared with CONT
within age groups was different (P < 0.02) between age groups. Indeed, peak C-peptide concentrations for the
first phase were lower (P < 0.05)
when ECC was compared with CONT among the older subjects (0.93 ± 0.16 vs. 1.12 ± 0.11 nM; ECC vs. CONT). Insulin AUC response for
the first and second phases and the C-peptide AUC response for the second phase, when ECC was compared with CONT, were similar in both
groups, with no age group differences (Table 2). Second-phase peak
C-peptide concentrations (for 150-180 min) were different (P < 0.05) between young (1.65 ± 0.16 vs. 1.41 ± 0.19 nM; ECC vs. CONT) and older (1.53 ± 0.23 vs. 1.68 ± 0.23 nM; ECC vs. CONT) groups.
C-peptide-to-insulin (CPI) molar ratios were calculated from AUC values
for insulin and C-peptide (34). The response of CPI ratios (Table 2)
was similar between groups for CONT clamps (CPICONT) and within age groups
when ECC was compared with CONT (CPIECC
CPICONT) for the first and
second phases. However, the response of CPI ratios
(CPIECC
CPICONT) was different
(P < 0.05) between young and older
subjects for the first but not the second phase.
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Glucose. Mean plasma glucose concentrations during the first 15 min (0-15 min) of the ECC and CONT clamps were 8.9 ± 0.2 and 8.8 ± 0.2 mM, respectively, for the young and 8.5 ± 0.2 and 8.5 ± 0.1 mM for the older subjects. Mean plasma glucose concentrations were maintained at 10.0 ± 0.1 mM during the last 165 min (15-180 min) of all clamps. Coefficients of variation (15-180 min) for the ECC and CONT clamps were 4.6 ± 0.5 and 4.6 ± 0.5%, respectively, for the young and 4.5 ± 0.5 and 5.0 ± 0.5% for the older subjects.
Glucose disposal rates (M values, calculated from the glucose infusion rates) for 15-180 min were not different between ECC and CONT clamps in either young (7.1 ± 0.6 vs. 7.8 ± 0.6 mg · kg FFM ![]() |
DISCUSSION |
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The principal finding in this investigation was an age-related
difference in the pancreatic -cell response to hyperglycemia after
the physiological stress induced by ECC. After ECC, healthy sedentary
young subjects showed an ~16% increase in the first-phase C-peptide
AUC above control, indicating an increase in the pancreatic
-cell
response to glucose that is consistent with previous findings by Kirwan
et al. (21) and King et al. (20). In contrast, healthy sedentary older
subjects did not show an increase in the first-phase C-peptide response
to hyperglycemia. Indeed, first-phase peak C-peptide concentrations in
the older subjects suggest that the increase in
-cell response to
hyperglycemia was ~11% lower after ECC compared with control. The
percent changes in insulin and C-peptide response to hyperglycemia
indicate that young and older subjects show opposite trends in
-cell
secretion after ECC for both the first and second phases (Fig. 2). Our
data suggest a pancreatic
-cell dysfunction in healthy older
individuals that prevents the "normal" increase in
-cell
secretion after a physiological stress such as ECC.
The older subjects tested in this study had fasting
glucose/insulin/C-peptide levels similar to those of young subjects.
Moreover, the older subjects exhibited a normal pancreatic -cell
response to a similar glycemic stimulus as young subjects during
control clamps. These data are in contrast to previous suggestions of abnormal basal (14, 32), first- (32), and second-phase (5, 11)
-cell
secretion with aging. However, subject composition and the control of
activity/diet may account for the discrepancy in findings. In the
present investigation, the older group had a normal oral glucose
tolerance test, and subjects were free from medication and
acute/chronic disease. In addition, our older subjects were physically
inactive for
6 mo before testing and had activity levels similar to
those of sedentary young subjects. Physical activity was controlled
before testing through residence at the GCRC, and a standard diet was
provided to maintain adequate carbohydrate storage. Given the imposed
restrictions, our data suggest that, with advancing age, normal glucose
tolerance and
-cell response to hyperglycemia may be inadequate
clinical predictors of normal
-cell secretory capacity under the
combined conditions of hyperglycemia and the physiological stress
associated with ECC. Hence, although adjustments in
-cell secretion
with increasing age help to maintain glucose tolerance, older
individuals may be predisposed to an eventual loss in reserve capacity
of the pancreas with further advances in age.
All subjects experienced significant whole body muscle soreness and
apparent muscle damage after ECC, with no age-related differences in
the response to exercise. Elevated muscle soreness ratings, muscular
stiffness, and inflammation 24-48 h after exercise suggest that
all subjects exhibited delayed onset muscle soreness, a symptom of
exercise-induced muscle damage (17). It has been shown that augmented
plasma CK levels after intense lengthening contractions are associated
with myofibrillar disruption and increased membrane permeability (31).
Thus, in the present study, elevated plasma CK concentrations in both
groups provide additional support for the presence of exercise-induced
muscle damage. Elevations in plasma CK levels have been reported
previously in young subjects with ECC-induced increases in -cell
secretion (20, 21).
Dynamic forced lengthening contractions have been shown to induce
transient whole body insulin resistance and decreased glucose uptake in
young individuals (3, 22). In the current study, glucose disposal rates
(M and M-to-I ratios) were not altered by ECC, which is consistent with
other data from hyperglycemic clamps (20, 21). Assessments of insulin
action using hyperglycemic clamp-derived glucose disposal rates are
inaccurate because of variability in the metabolism of infused glucose,
incomplete suppression of hepatic glucose production by portal insulin,
and the possible contributions of non-insulin-mediated glucose
disposal. Indeed, studies using euglycemic hyperinsulinemic clamps (3,
22) quantitatively demonstrate reductions in whole body glucose
disposal rates and thus insulin resistance in young subjects after
unaccustomed ECC. Hence, the increase in pancreatic -cell secretion
in young subjects after ECC in the present study and other studies (20, 21) may be the normal
-cell compensation in response to a
physiological stress at the muscle that mimics a state of insulin
resistance. Moreover, similar increases in
-cell response have been
observed after nicotinic acid-induced insulin resistance in young
subjects (18).
In contrast, when healthy older subjects are presented with a
combination of hyperglycemia and ECC, they demonstrate an inability of
the pancreas to alter -cell responsivity. ECC was used as a
physiological stress in an attempt to study stress-mediated alterations
in
-cell secretion with human aging. Other physiological stressors
with increasing age include insulin resistance, type 2 diabetes, and
obesity. The current findings are perplexing in light of previous data
showing that the
-cell of older subjects adapts to the stress
associated with aerobic exercise in a manner comparable to young
subjects (23). In this study, healthy older subjects show a
-cell
response to ECC-induced stress similar to that observed in other
conditions of physiological stress. Moreover, it is not apparent why
the observed decrements in
-cell secretion are pronounced during the
first phase, rather than the second phase.
-Cell decompensation
occurs during the transition toward type 2 diabetes, in which the first
phase is either reduced (33, 41) or may show a paradoxical fall below
basal (26). A specific first-phase
-cell dysfunction has been
previously noted with aging (8) and may predict the onset of type 2 diabetes in prediabetic IGT patients (37). Likewise, trends toward
blunted second-phase secretion are seen with IGT (5) and type 2 diabetes (41). In the present investigation, the decline in
-cell
responsivity in older subjects after ECC-induced stress may suggest a
mechanism that temporarily parallels the metabolic state associated
with insulin resistance. Furthermore, the vulnerability of the first phase to physiological stressors such as type 2 diabetes and
exercise-induced muscle damage may suggest a metabolic disorder of this
initial secretory response common to both conditions.
The observed group differences in C-peptide response after ECC, in
conjunction with a similar insulin response, beg the question of
age-related differences in insulin/C-peptide clearance from circulation. The pancreas secretes equimolar amounts of insulin and
C-peptide into the portal circulation (6). The liver extracts a
significant portion of the insulin but not the C-peptide during the
clamp procedure (34). The relative molar quantities of insulin and
C-peptide in peripheral circulation (CPI ratios) have been used as an
index of hepatic insulin clearance (34). In the present study, CPI
ratios suggest that both groups had similar insulin clearance during
CONT clamps. However, older subjects exhibited a significantly
different first-phase CPI ratio response
(CPIECC CPICONT) compared with the
young. Although not significant, the change in CPI ratios
(CPIECC vs.
CPICONT) in young (+16 and +15%; first and second phases, respectively) and older subjects (
14 and
5%; first and second phases, respectively)
suggests opposite group trends. Whereas the young increased, the older subjects may have decreased hepatic insulin clearance after ECC, particularly during the first phase. Abnormalities in hepatic insulin
extraction have been seen in other conditions of physiological stress,
such as obesity (35) and type 2 diabetes (38). In addition, it has been
suggested that renal clearance of C-peptide is altered after exercise
(19). Although a previous study showed no significant changes in renal
C-peptide clearance after ECC (21), the reported ~38% decrease in
the mean urinary C-peptide concentrations suggests some role for renal
clearance. In the present study, the contributions of hepatic and renal
clearance mechanisms may explain why similar circulating insulin levels were maintained in both groups, despite differences in C-peptide. Our
findings suggest that aging is associated with abnormal clearance of
insulin and/or C-peptide after exercise-induced muscle damage, perhaps via hepatic and/or renal mechanisms.
Body composition may account for some of the differences in -cell
response to hyperglycemia after ECC between groups. Although body mass
index was similar, the older group had more body fat compared with the
young group. Furthermore, the WHR data indicate that older subjects had
greater upper body fat distribution. However, it is important to note
that the older subjects were not obese on the basis of either total or
regional adiposity. Pancreatic
-cell secretion before exercise was
not related to body composition. However, the C-peptide response to ECC
(C-peptide AUCECC
C-peptide AUCCONT) was inversely
related to WHR but not percent body fat. These data indicate that, with
advancing age, the reduced ability to increase
-cell secretion after
ECC may be related to an increase in abdominal adiposity but not total
adiposity. There is growing evidence linking the accumulation of
abdominal fat to disturbances in glucose metabolism and insulin action
(23, 25). Albeit the relationship between body fat distribution and
-cell secretory response has received little attention, Walton et
al. (40) have suggested that central adiposity is associated with
abnormal insulin and C-peptide secretion. Although the effects of
abdominal adiposity on pancreatic
-cell function after ECC were not
a primary question, our observations contribute to previous findings
regarding central obesity, insulin resistance, and abnormal
-cell
secretion.
The mechanisms responsible for the age-associated decline in -cell
responsivity after ECC are not apparent. An unidentified factor(s)
related to exercise-induced muscle damage, or resultant insulin
resistance (3, 22), may act on the pancreas to increase
-cell
secretion in young individuals. Thus it is possible that older
individuals possess an acute pathophysiological maladaptation under
which 1) the
-cell may be less
sensitive to a potential physiological signal(s),
2) this signal(s) may also act on
the liver/kidney to affect insulin/C-peptide clearance, and
3) the accumulation of abdominal fat
may potentially affect this signaling mechanism(s). Exercise-induced
muscle injury has been shown to initiate an immune response
(acute-phase response), mediated by cytokines such as interleukin
(IL)-1, IL-6, and tumor necrosis factor (TNF)-
(7). Recent reports
indicate that TNF-
may be associated with insulin resistance (16)
and altered
-cell secretion (28). Thus increases in TNF-
or other
cytokines after ECC could contribute to the observed changes in
-cell responsivity. King et al. (20) proposed that ECC-mediated
increases in IL-1
may stimulate
-cell secretion, as reported
previously in an animal model (13). Although free fatty acids have also
been reported to induce insulin resistance and stimulate
-cell
secretion (4), free fatty acid levels remain unchanged 48 h after ECC
(22). Neural or hormonal changes may be potential stimuli. However, Kirwan et al. (22) showed no change in plasma glucagon, cortisol, epinephrine, and norepinephrine levels 48 h after ECC. Therefore, numerous mechanisms may be responsible for signaling between the muscle, pancreas, liver, or kidney after a physiological stress such as
exercise. With advancing age, an abnormality in these potential
pathways may be responsible for the observed differences, with some
contribution arising from increased abdominal adiposity.
In summary, this is the first study to examine the effects of ECC on
the pancreatic -cell response to hyperglycemia in older individuals.
In healthy sedentary young individuals, an increase in
-cell
sensitivity to glucose serves as a normal adaptation to either ECC per
se or a phenomenon related to transient insulin resistance (3, 22).
Although healthy sedentary older individuals may maintain apparently
normal glucose tolerance and
-cell secretion, they exhibit a decline
in
-cell function that is revealed when presented with the combined
conditions of hyperglycemia and the physiological stress of
exercise-induced muscle damage. The observed age-related maladaptations
specific to C-peptide may have metabolic significance in light of
emerging findings suggesting that C-peptide may assist in skeletal
muscle glucose uptake in healthy young individuals but may be defective
in both type 2 diabetics and nondiabetic healthy older individuals
(39). In addition, abnormal insulin and/or C-peptide clearance
may also play a role, potentially through hepatic and/or renal
mechanisms. Thus a secretion/clearance paradigm that is involved in
other metabolic states, such as aging, obesity, type 2 diabetes, and
exercise, may also apply to the ECC/muscle damage model. However, the
relative contributions of
-cell secretion and subsequent clearance
to the metabolic abnormalities observed in this study are not clear.
Furthermore, our data linking the
-cell decompensation to abdominal
adiposity provide a critical experimental base to examine relationships
between regional adiposity and
-cell function with advancing age. We
conclude that human aging is associated with a decline in the
pancreatic
-cell responsivity after the physiological stress
associated with ECC.
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ACKNOWLEDGEMENTS |
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We thank the nursing/dietary staff of the GCRC and the technical/engineering staff of the Noll Physiological Research Center for supporting the implementation of the study and assisting with data collection. We are also grateful to Allen R. Kunselman at the Center for Biostatistics and Epidemiology at the Hershey Medical Center for assistance in data analysis and interpretation. Furthermore, we extend special thanks to Dariush Elahi for helpful advice in the setup of the hyperglycemic clamp procedure and to Peter A. Farrell for thoughtful input throughout the course of the investigation and the preparation of the manuscript. We also wish to thank Christiana Lakatta, Matthew Wells, and Wendy Heslin for assistance in the project. Finally, we thank the research volunteers for cooperation and commitment to the project.
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FOOTNOTES |
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This research was supported by National Institute on Aging Grant AG-12834-02 and the Interdisciplinary Seed Grant from the College of Health and Human Development at The Pennsylvania State University (to J. P. Kirwan), National Institute on Aging Grant AG-11811-04 (to W. J. Evans), and GCRC Grant RR-10732-02.
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. §1734 solely to indicate this fact.
Address for reprint requests: J. P. Kirwan, Noll Physiological Research Center, 105 Noll Laboratory, The Pennsylvania State Univ., University Park, PA 16802.
Received 21 January 1998; accepted in final form 11 June 1998.
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