Division of Endocrinology, Diabetes and Metabolism, Division of Geriatrics, General Clinical Research Center, and Diabetes Research and Training Center, Washington University School of Medicine, St. Louis, Missouri 63110
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ABSTRACT |
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To test the
hypothesis that glycemic sensitivity to epinephrine is reduced in older
individuals and to assess the impact of a sedentary lifestyle on
responses to the hormone, we performed 30-min sequential intravenous
infusions of epinephrine (0, 41, 82, 164, 246, and 328 pmol · kg1 · min
1)
in young (n = 10) and older
(n = 23) healthy subjects. We
performed these again after 12 mo of physical training, which raised
peak O2 consumption from 24.4 ± 1.0 to 30.4 ± 1.4 ml · kg
1 · min
1
(P < 0.01) in most of the older
subjects (n = 21). During epinephrine infusions, plasma epinephrine concentrations were higher
(P = 0.0001) in older than in young
subjects (e.g., final values of 7,280 ± 500 vs. 4,560 ± 380 pmol/l,
respectively), indicating that the clearance of epinephrine from the
circulation was reduced in the older individuals. Plasma epinephrine
concentration-response curves disclosed reduced glycemic sensitivity to
the hormone in the older subjects (P = 0.0001), a finding plausibly attributed to increased sympathetic neural
activity, as evidenced here by higher plasma norepinephrine
concentrations (P = 0.0001) in the older subjects and consequent desensitization of cellular
responsiveness to catecholamines. Training did not correct reduced
epinephrine clearance, reduced glycemic sensitivity to epinephrine, or
raised norepinephrine levels. We conclude that aging is associated with reduced clearance of epinephrine from the circulation and reduced glycemic sensitivity to epinephrine, the latter plausibly attributed to
an age-associated increase in sympathetic neural norepinephrine release. These age-associated changes are not the result of a sedentary lifestyle.
aging; glucose
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INTRODUCTION |
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THE ADRENOMEDULLARY HORMONE EPINEPHRINE and the
sympathetic postganglionic neurotransmitter norepinephrine exert an
array of hemodynamic and metabolic effects (5). The latter include increments in plasma glucose concentrations. Epinephrine raises plasma
glucose concentrations by both stimulating glucose production and
limiting glucose utilization. It does so through both direct (2-adrenergic) and indirect
(other hormone or substrate mediated) actions; the latter include
(
2-adrenergic) limitation of
insulin secretion (5). The mechanisms of the glycemic action of
norepinephrine are thought to be similar to those of epinephrine (5).
Aging is associated with reduced hemodynamic responses to
-adrenergic (2-4) and
-adrenergic (12, 38) agonists. Reduced catecholamine-stimulated lipolysis has also been reported (20). The
precise mechanism(s) of this age-associated reduced responsiveness to
catecholamines is not known.
Age-associated changes in the physiology of the sympathochromaffin (sympathoadrenal) system have been studied rather extensively (see review in Ref. 9). Elevated plasma norepinephrine concentrations (9, 22, 24, 25, 28, 30, 33, 40), norepinephrine spillover rates (9, 22, 24, 25, 40), and muscle sympathetic nerve activity measured with microneurography (14, 26, 37) provide strong evidence that sympathetic neural norepinephrine release increases with age. An age-related decrease in norepinephrine clearance has also been found in several studies (9, 22, 24, 25, 40). In contrast, plasma levels of the adrenomedullary hormone epinephrine do not increase with age (8, 25, 30), and isotopically determined epinephrine secretion rates have been found to be comparable (25) or decreased (8) in older compared with young subjects. Epinephrine clearance has also been reported to be comparable (25) or decreased (8) in older compared with young subjects. Interestingly, however, venous plasma epinephrine concentrations have been reported to be lower during epinephrine infusions in older subjects (42), a finding implying increased clearance of the hormone. Clearly, this issue is relevant to attempts to define glycemic sensitivity to epinephrine by infusion of the hormone in vivo.
To test the hypothesis that glycemic sensitivity to epinephrine is
reduced in older individuals, we performed 30-min sequential intravenous infusions of epinephrine in increasing doses (0, 41, 82, 164, 246, and 328 pmol · kg1 · min
1)
known to produce plasma epinephrine concentrations that span the
physiological range and raise plasma glucose concentrations (3, 4) in
young and older healthy human subjects. We speculated that an
age-associated decrease in glycemic sensitivity, if found, might be a
reflection of an age-associated decrease in physical fitness.
Therefore, to assess the impact of increased fitness on the responses
to epinephrine, most of the older subjects were restudied after 12 mo
of physical training.
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METHODS |
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Subjects. Ten healthy young subjects and 23 healthy older subjects gave their written consent to participate in this study, which was approved by the Washington University Human Studies Committee and conducted in the outpatient facility of the Washington University General Clinical Research Center. Twenty-one of the older subjects were restudied after physical training.
The mean (±SD) age of the ten young (Y) subjects (7 women, 3 men) was 22.9 ± 1.7 yr. Their mean body weight was 69.4 ± 13.6 kg, mean percent body fat 21.5 ± 3.0%, and mean peak O2 consumption (Experimental protocol.
Subjects were studied in the morning after an overnight fast and were
in the supine position throughout. Intravenous lines were inserted in
an antecubital vein (for infusions) and a hand vein, with that hand
kept in an ~55°C box (for arterialized venous blood sampling). In
the elderly subject groups, a primed (20 µCi), continuous (0.2 µCi/min) infusion of
[3-3H]glucose (Du
Pont-NEN, Boston, MA) was begun at 90 min and continued through
+180 min (the end of the experiment) to permit calculation of rates of
glucose production (Ra, rate of
appearance) and glucose utilization
(Rd, rate of disappearance) (28,
29). Saline was infused intravenously from 0 to 30 min (0 epinephrine
dose), and epinephrine (epinephrine injection, Elkins-Sinn, Cherry
Hill, NJ) was then infused sequentially over 30-min periods in doses of
41, 82, 164, 246, and 328 pmol · kg
1 · min
1
(7.5, 15, 30, 45, and 60 ng · kg
1 · min
1).
Arterialized venous blood samples were drawn at 20, 25, and 30 min into
each 30-min infusion. Blood pressures and heart rates were recorded
(Dynamap, Critikon, Tampa, FL) at the same time points.
Analytic methods.
Plasma glucose was measured with a glucose oxidase method (Beckman
Glucose Analyzer 2, Beckman Instruments, Fullerton, CA). Plasma
epinephrine and norepinephrine concentrations were measured with a
single isotope-derivative (radioenzymatic) method (34); those of
insulin (15), C-peptide (15), glucagon (7), cortisol (10), and growth
hormone (32) were measured with radioimmunoassays. Serum nonesterified
fatty acid concentrations were measured with an enzymatic colorimetric
method (13), and blood -hydroxybutyrate (29), lactate (21), and
alanine (2) levels were measured with enzymatic techniques.
Statistical methods. Data are expressed as means ± SE except where the standard deviation (SD) is specified. Data were first analyzed by repeated-measures analysis of variance and analysis of covariance (with the plasma epinephrine concentration as the covariate, e.g., for the responses to epinephrine). Groups (Y vs. OUT, OUT vs. OT) were then compared by multivariate repeated-measures analysis of variance. These analyses require complete data sets for a given parameter. Therefore, the numbers of subjects analyzed for each parameter are specified in Tables 1-4 and Figs. 1-4. P values <0.05 were considered to indicate significant differences.
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RESULTS |
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In addition to increments in plasma epinephrine concentrations (Fig.
1), epinephrine infusions were associated
with significant (P = 0.0001)
increments in plasma glucose concentrations (Fig. 2), glucose production (Table
1), serum nonesterified fatty acid concentrations (Fig. 3), blood
-hydroxybutyrate and lactate concentrations (Table
2), plasma cortisol (Table
3) and norepinephrine (Fig. 4)
concentrations, and heart rates (Table 4),
as well as decrements in diastolic blood pressure (Table 4). Glucose
utilization (Table 1), blood alanine concentrations (Table 2), plasma
insulin, glucagon, and growth hormone concentrations (Table 3), plasma C-peptide levels (data not shown), and systolic blood pressures (Table
4) did not change significantly, although the latter appeared to
increase in the young subjects (Table 4).
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There were significant (P = 0.0001) group differences and infusion × group interactions in the plasma epinephrine concentrations during the epinephrine infusions (Fig. 1). Plasma epinephrine concentrations rose to higher levels in the older subjects (both OUT and OT) compared with the young subjects. Despite these higher plasma epinephrine concentrations, increments in plasma glucose concentrations were significantly (P = 0.0001) lower in the older subjects (Fig. 2), and there was a significant (P = 0.0090) infusion × group interaction by analysis of covariance (i.e., after adjustment for plasma epinephrine concentrations).
There were also significant (P = 0.0001) group differences in the serum nonesterified fatty acid (and
blood -hydroxybutyrate) concentrations during the epinephrine
infusions (Fig. 3, Table 2). In this instance, however, serum
nonesterified fatty acid levels were higher in the older subjects (at
least the OUT subjects). Blood lactate and alanine concentrations did
not differ among the groups (Table 2). Insulin and growth hormone
levels were lower and glucagon levels were higher early on, and there
were late increments in cortisol levels in the older subjects (Table 3). Plasma norepinephrine concentrations were higher throughout in the
older subjects (Fig. 4).
Heart rates were similar in the Y and OUT subjects (Table 4). Systolic and diastolic blood pressures were higher early on in the older subjects (Table 4).
Twelve months of physical training of older subjects raised their peak
O2 values from 24.4 ± 1.0 to 30.4 ± 1.4 ml · kg
1 · min
1
(P < 0.01). Training was associated
with changes in several endocrine-metabolic parameters. During
epinephrine infusions, plasma glucose concentrations were slightly
lower (P = 0.0450; Fig. 2), rates of
glucose production (P = 0.0120) and
utilization (P = 0.0005) were higher
(Table 1), and serum nonesterified fatty acid concentrations were lower
(P = 0.0110; Fig. 3, Table 2). Plasma
insulin concentrations were not significantly lower; plasma C-peptide
concentrations were significantly (P = 0.0260) lower (data not shown). Heart rates were also lower
(P = 0.0070; Table 4). Nonetheless,
during epinephrine infusions, plasma epinephrine concentrations were
similar before and after training and remained higher than the levels
observed in young subjects (Fig. 1), plasma glucose concentrations were not increased to the levels observed in young subjects (Fig. 2), and
plasma norepinephrine concentrations were not reduced to the levels
observed in young subjects (Fig. 4).
Statistical analyses of the main outcome variables are summarized in Table 5.
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DISCUSSION |
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These data document reduced glycemic sensitivity to epinephrine in older individuals, a finding that is not attributable to a sedentary lifestyle. They also indicate that the clearance of epinephrine from the circulation is reduced in older individuals.
At a given intravenous epinephrine infusion rate, plasma epinephrine concentrations were ~50% higher in the older compared with the young subjects. This evidence that the clearance of epinephrine from the circulation is reduced is consistent with the finding of Esler et al. (8) of reduced basal epinephrine clearance in older individuals, and perhaps it is not incompatible with the finding of Morrow et al. (25), by use of tracer techniques, of unaltered basal epinephrine clearance in older subjects. It is, however, incompatible with the report of increased clearance of infused epinephrine in older subjects (42). The basis of this discrepancy is unclear, but it is perhaps relevant that the latter investigators measured venous plasma epinephrine concentrations (42), whereas we measured arterialized venous epinephrine levels. Nonetheless, the present data indicate that there is an age-associated decrease in the whole body clearance of epinephrine, like that of norepinephrine (9, 22, 24, 25, 40). Clearly, therefore, administered dose-response curves cannot be used to assess sensitivity to epinephrine in older compared with young subjects. Rather, plasma epinephrine concentration-response curves must be used.
Plasma glucose concentrations rose to similar levels during epinephrine infusions in the young and the older subjects. However, the slope of the relationship between increasing plasma epinephrine and plasma glucose concentrations was less steep in the older subjects. Thus plasma epinephrine concentration-response curves demonstrated lesser increments in plasma glucose (and perhaps blood lactate, P = 0.0700) concentrations during epinephrine elevations in the older compared with the young subjects. Therefore, glycemic (and perhaps glycolytic) sensitivity to epinephrine is reduced in older individuals.
Among the key glucoregulatory hormones (5), plasma insulin levels were lower and did not increase disproportionately during epinephrine infusions in the older subjects. Thus the finding of reduced glycemic sensitivity to epinephrine cannot be attributed to hyperinsulinemia. Plasma glucagon and cortisol concentrations were higher (and cortisol concentrations increased at the higher epinephrine levels) in the older subjects; plasma growth hormone levels were similar in the two groups. Thus reduced glycemic sensitivity to epinephrine cannot be attributed to decreased glucagon, cortisol, or growth hormone levels. Therefore, alterations in the glucoregulatory hormonal environment do not explain the finding of reduced glycemic sensitivity to epinephrine in older individuals.
Plasma norepinephrine concentrations were higher throughout in the
older subjects, as expected (9, 22, 24, 25, 28, 30, 33, 40). Although
the extent to which decreased clearance of the neurotransmitter
contributes to this is debated, there is substantial evidence that
this reflects increased sympathetic neural activity (9,
22, 24, 25, 40), as documented directly by microneurography (14, 26,
37) in older individuals. To the extent that chronically increased
sympathetic neural norepinephrine release results in desensitization of
the 2-adrenergic receptors that
mediate the direct glycemic actions of epinephrine in relevant target
tissues (5), increased sympathetic neural activity provides a plausible
mechanism for the finding of reduced glycemic sensitivity to
epinephrine in older individuals.
Lipolytic sensitivity to epinephrine, as assessed by serum
nonesterified fatty acid concentrations, was not found to be reduced in
the older subjects. Indeed, the response appeared to be increased in
the untrained older subjects. However, because nonesterified fatty
acids are subject to reesterification, their serum levels are an
imperfect index of lipolysis. Furthermore, the epinephrine doses
infused, which were selected to examine the glycemic response, resulted
in plasma epinephrine concentrations largely at the top of the plasma
epinephrine concentration-nonesterified fatty acid response curve (17).
Taken at face value, how could the absence of reduced lipolytic
sensitivity to epinephrine in older individuals be rationalized with
the finding of reduced glycemic sensitivity to the hormone and its
putative mediation by increased sympathetic neural activity? The fact
that increased sympathetic neural activity would be expected to
desensitize 1- and
2-adrenergic receptors to a
greater extent than
3-adrenergic receptors (16),
which also mediate the lipolytic response to epinephrine (6, 19), might
explain these findings.
Physical training of elderly subjects improved fitness and altered several endocrine-metabolic parameters. During epinephrine infusions, plasma glucose concentrations and insulin secretion were reduced, glucose turnover was increased, and nonesterified fatty acid concentrations and heart rates were lower. However, reduced clearance of epinephrine from the circulation, reduced glycemic sensitivity to epinephrine, and raised plasma norepinephrine concentrations were unaltered by training. Thus these are not the result of a sedentary lifestyle.
In summary, aging is associated with decreased clearance of epinephrine from the circulation and reduced glycemic sensitivity to epinephrine. The latter is plausibly attributed to an age-associated increase in sympathetic neural activity.
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ACKNOWLEDGEMENTS |
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We acknowledge the technical assistance of Suresh Shah, Goeffry Boyd, Krishan Jethi, Susan Allen, Bernard Zickmund, Alka Bansal, Shirley Hill, Joy Brothers, Bakula Trivedi, Greg Winter, and the nursing staff of the Washington University General Clinical Research Center. Kay Kerwin prepared the manuscript.
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FOOTNOTES |
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Current address for J. C. Marker: University of Wisconsin-Green Bay, 2420 Nicolet Dr., Green Bay, WI 54311-7001.
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: P. E. Cryer, Division of Endocrinology, Diabetes and Metabolism, Washington Univ. School of Medicine (Campus Box 8127), 660 South Euclid Ave., St. Louis, MO 63110.
Received 23 April 1998; accepted in final form 16 July 1998.
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