Epinephrine effects on insulin-glucose dynamics: the
labeled IVGTT two-compartment minimal model approach
Paolo
Vicini1,
Angelo
Avogaro2,
Mary
E.
Spilker1,
Alessandra
Gallo2, and
Claudio
Cobelli3
1 Department of Bioengineering, University of
Washington, Seattle, Washington 98195; 2 Departments of
Metabolic Diseases and 3 Electronics and Informatics,
University of Padova, 35128 Padua, Italy
 |
ABSTRACT |
The hyperglycemic effects of
epinephrine (Epi) are established; however, the modulation of
Epi-stimulated endogenous glucose production (EGP) by glucose and
insulin in vivo in humans is less clear. Our aim was to determine the
effect of exogenously increased plasma Epi concentrations on insulin
and glucose dynamics. In six normal control subjects, we used the
labeled intravenous glucose tolerance test (IVGTT) interpreted with the
two-compartment minimal model, which provides not only glucose
effectiveness (S
), insulin sensitivity
(S
), and plasma clearance rate (PCR) at basal state,
but also the time course of EGP. Subjects were randomly studied during
either saline or Epi infusion (1.5 µg/min). Exogenous Epi infusion
increased plasma Epi concentration to a mean value of 2,034 ± 138 pmol/l. During the stable-label IVGTT, plasma glucose, tracer glucose,
and insulin concentrations were significantly higher in the Epi study.
The hormone caused a significant (P < 0.05) reduction in
PCR in the Epi state when compared with the basal state. The
administration of Epi has a striking effect on EGP profiles: the nadir
of the EGP profiles occurs at 21 ± 7 min in the basal state and
at 55 ± 13 min in the Epi state (P < 0.05). In
conclusion, we have shown by use of a two-compartment minimal model of
glucose kinetics that elevated plasma Epi concentrations have profound
effects at both hepatic and tissue levels. In particular, at the liver
site, this hormone deeply affects, in a time-dependent fashion, the
inhibitory effect of insulin on glucose release. Our findings may
explain how even a normal subject may have the propensity to develop
glucose intolerance under the influence of small increments of Epi
during physiological stress.
insulin action; endogenous glucose production; glucose
effectiveness
 |
INTRODUCTION |
THE AUTONOMIC NERVOUS
SYSTEM modulates glucose and fat metabolism through both direct
neural effects and hormonal effects. In humans, epinephrine (Epi)
stimulates lipolysis, ketogenesis, thermogenesis, and glycolysis and
raises plasma glucose concentrations by stimulating both glycogenolysis
and gluconeogenesis (9). At the liver site, Epi increases
hepatic glucose production either directly by stimulating
glycogenolysis or indirectly by increasing gluconeogenesis, which is
responsible for 60% of the overall increase in hepatic glucose
production (19). These effects are exerted through both
- and
-adrenergic stimuli (20, 21).
Although the hyperglycemic effects of Epi on the liver are firmly
established, less clear is the modulation of Epi-stimulated endogenous
glucose production (EGP) by insulin in vivo in humans. In rat studies,
it was shown that, when Epi is combined with insulin infusion, there is
a 50% reduction in liver glycogen content with evidence for a
transient activation of hepatic glucose output by Epi in the initial 60 min of its exposure (15). In hepatocytes isolated from
lean rats, the presence of insulin in the incubation medium antagonizes
in a concentration-dependent manner the stimulation of gluconeogenesis
by Epi (24). Although the immediate effect of Epi is the
ability to prevent a compensatory increase in
-cell secretion, the
ongoing hyperglycemia overcomes the Epi-mediated inhibition on insulin
secretion so that compensatory hyperinsulinemia limits the excessive
rise in plasma glucose. This fine modulation is absent in
insulin-dependent diabetic patients and explains both the exaggerated
hyperglycemic and lipolytic responses during an Epi infusion in these
patients (9).
Taken together, these data suggest the existence of a fine,
time-dependent interaction between Epi and insulin in determining EGP.
However, this interplay has never been precisely assessed in vivo, in
humans, because of the inability of the available approaches to
properly describe this relationship, particularly in response to a
glucose load. This is particularly important, because this situation is
rather common in daily life: it is well known that even a normal
subject has the propensity to develop glucose intolerance during
physiological stress (13).
In light of these premises, our aim was to determine the effect of
exogenously increased plasma Epi concentrations on insulin and glucose
dynamics. We did so by using the labeled intravenous glucose tolerance
test (IVGTT) interpreted with the two-compartment minimal model
(7, 30). This approach provides not only important indexes
like glucose effectiveness (S
), insulin sensitivity
(S
), and plasma clearance rate (PCR) at basal state,
but also the time course of EGP, thus allowing us to unravel the
temporal interaction among Epi, glucose, and insulin in the modulation
of the EGP.
 |
MATERIALS AND METHODS |
Subjects.
A stable isotopically labeled IVGTT was performed in six normal healthy
volunteers (3 males and 3 females) who participated in the study after
giving written informed consent. They were 24 ± 3 yr old, and
their body mass index was 23 ± 2 kg/m2. The subjects
were in good health. For
3 days before the study, each subject
consumed a diet containing >250 g carbohydrate; this amount was
verified by a dietitian.
Experimental procedures.
On the day of the study, at 7:00 AM after an overnight fast, the
subjects were admitted to the Divisione di Malattie del Metabolismo of
the University of Padova. The experimental protocol was approved by the
Ethical Committee of the University Hospital of Padova. A 20-gauge
butterfly needle was inserted into a dorsal hand vein at 7:30 AM. An
18-gauge cannula was then placed into the contralateral antecubital
vein for injection of the labeled glucose load and Epi infusion. On one
occasion (Epi study), starting at 8:00 AM, they received a continuous
infusion of Epi at a rate of 1.5 µg/min (8.2 mmol/min), which lasted
until 300 min (end of sampling). On another occasion, the control
study, saline was infused. The two studies were randomized and
performed
7 days apart. Epi was dissolved in saline solution in the
presence of ascorbic acid (0.5 mg/ml) to prevent oxidation. New Epi
solution was prepared every 2 h throughout the test. Ninety
minutes after the beginning of the Epi infusion, each subject received
an IVGTT labeled with the 6,6-2H2
isotopolog of glucose. The glucose bolus was administered from 30 to 60 s. The final concentration of deuterated glucose in each tracer (exogenous) solution was ~10% of the natural unlabeled glucose content. Blood samples were obtained before and during the Epi
infusion and before and during the IVGTT. After the IVGTT pulse,
samples were obtained at
30,
15, 0, 2, 3, 4, 5, 6, 8, 10, 12, 15, 20, 25, 30, 35, 40, 60, 80, 100, 120, 140, 180, 210, 240, and 300 min.
The samples for glucose, deuterated glucose, insulin, and C-peptide
determination were collected in tubes with EDTA-K3, whereas
those for Epi were collected with reduced glutathione and EDTA. They
were immediately centrifuged at 4°C and stored at
80°C until the assay.
Materials.
[2H2]glucose was purchased from MassTrace
(Woburn, MA). Chemical purity was verified by specific enzymatic
analysis with glucose oxidase. Sterility was verified by bacteriologic
analysis, and the material was shown to be pyrogen free. Before each
study, an appropriate amount of the labeled powder was dissolved in a sterile 50% glucose solution and then passed through a 0.22-µm Millipore filter into a sterile vial that was sealed until use.
Biochemical and stable isotope tracer analysis.
Plasma was separated and plasma glucose content determined
enzymatically with a glucose analyzer (Beckman, Fullerton, CA). In the
remaining plasma, insulin and C-peptide were assayed with specific
radioimmunoassay (16) and catecholamines with an HPLC method (14). Deuterated glucose was analyzed as a
pentaacetate derivative using a method previously described
(1). The samples were analyzed on a Hewlett-Packard 5988 Quadrupole gas chromatography-mass spectrometry instrument operated
in the electron impact mode by selected ion monitoring after isothermal
separation at 250°C on a 30-in. J & W capillary column. Glucose
pentaacetate isotopomers are monitored at mass-to-charge
(m/z) 242 and 244 for
[6,6-2H2]glucose and at m/z 243 for [6,6-2H1]glucose, as described
previously (1).
From ion intensity ratios, the value in the sample of the isotope ratio
R between labeled and unlabeled species is derived. For the
[6,6-2H2]glucose tracer,
[6,6-2H2]glucose and
[6,6-1H2]glucose are the labeled and
unlabeled species with, respectively, two 2H atoms or two
1H atoms in position 6. Species are thus
defined with reference to specific atoms in specific positions, and in
deriving R we correct analytically for interferences in the mass
spectrum from the natural isotopic composition of the other atoms of
the monitored ion (7).
The ratio Z between tracer and tracee mass (or
concentrations) in the sample can be evaluated from isotope ratio
measurements as
|
(1)
|
where G* is the tracer glucose concentration, that
is, the concentration in the sample of the exogenous administered
mixture of natural and deuterated glucose; Ge is the tracee
glucose concentration, that is, the concentration of endogenous natural
glucose. Two isotope ratios, R and R', can be defined. R is the ratio
of the mass of the labeled and unlabeled species, and R' is that of the incompletely labeled and unlabeled species. RI
(RI') and RN (RN') are isotope
ratios in a sample of pure tracer and tracee, respectively, and
R(t) is the isotope ratio measurement at each time
t (6).
The above approach based on calculating the Z
variable only requires the assumption of isotopic indistinguishability.
Assessment of glucose disposal by the two-compartment minimal
model.
The two-compartment minimal model (2CMM) was used to determine the
insulin and glucose dynamics for each individual in the basal and Epi
states. The model is based on fitting the following equations to
glucose data to obtain best-fit parameters and metabolic indexes for
the system (7, 31)
|
(2)
|
where Q
(t) and
Q
(t) denote tracer glucose
masses in the first (accessible pool) and second (slowly equilibrating)
compartments, respectively, (mg/kg for a stable-label IVGTT),
X(t) is insulin action (min
1),
I(t) and Ib are plasma insulin and basal (end of
test) insulin, respectively (µU/ml), G(t) is tracee
glucose concentration in the accessible pool (mg/dl),
G*(t) is plasma tracer glucose concentration
(mg/dl), D* is the exogenous glucose dose (mg/kg),
V1 is the volume of the accessible pool (dl/kg), and
k21 (min
1),
k12 (min
1),
k02 (min
1),
p2 (min
1), and sk
(ml · µU
1 · min
1) are
parameters describing glucose kinetics and insulin action. Gb is the basal (end of test) glucose concentration.
Glucose uptake by insulin-independent tissues is described as the sum
of a constant and a term proportional to glucose mass in the accessible
pool; the proportionality term kp is derived
from
and the constant component is defined by the parameter
Rd0, assumed known and equal to 1 mg · kg
1 · min
1. Other
derived parameters include glucose effectiveness, S
|
(3)
|
plasma glucose clearance rate at basal insulin, PCR
|
(4)
|
insulin sensitivity, S
|
(5)
|
and basal endogenous glucose production, EGPb
|
(6)
|
It is also possible to derive an estimate of the time-varying
plasma glucose clearance rate during the test, PCR(t)
|
(7)
|
The 2CMM was run for each individual in the control study and
after 90 min of epinephrine infusion. Curve fitting of the model
prediction with the measured concentration values was accomplished via
nonlinear weighted least squares by use of SAAM II software (SAAM
Institute and University of Washington, Seattle, WA, 1998, http://www.saam.com) on a PC (4). The fractional
standard deviation was calculated for each data point by use of error
propagation from the isotope ratio measurements, and the weights were
calculated from the measured values. This allowed us to calculate the
precision of subject-specific estimates of all model parameters.
EGP estimation by the nonparametric stochastic deconvolution
method.
EGP was calculated by nonparametric stochastic deconvolution. EGP,
endogenous glucose concentration Ge(t)
calculated as total glucose minus exogenous, i.e., tracer + cold bolus
glucose, and the impulse response of the system given by the 2CMM
[indicated here by h(t,
), as this is a time-varying
model] are related through the following integral equation
|
(8)
|
The deconvolution yields a time course of EGP for each subject
in the basal and Epi states (see Table 1). The time course was
calculated every 2 min, yielding an almost continuous prediction. This
method of reconstructing endogenous production during an IVGTT was
independently validated by using the tracer-to-tracee clamp described
in Ref. 32.
The deconvolution programs were written in Matlab (The MathWorks,
Natick, MA) and executed on a PC (31).
Statistics.
To evaluate the differences between the control and Epi states, the
Wilcoxon signed-ranks test for matched pairs (2-tailed) was employed,
and a P value of <0.05 was considered to be significant. This statistical test was chosen on the basis of the paired nature of
the data and the small sample size. Test statistics were computed with
the statistical software SPSS Rel. 10.0.5 (SPSS, Chicago, IL). Values
are reported as means ± SE, except where otherwise stated.
 |
RESULTS |
Epinephrine, glucose, insulin, and C-peptide concentrations.
Baseline plasma Epi concentration was 520 ± 48 pmol/l. Exogenous
Epi infusion increased plasma Epi concentration to a mean value of
2,034 ± 138 pmol/l (P < 0.001). The coefficient of
variation (SD/mean × 100) of Epi concentrations during the IVGTT
time course was 14 ± 6% during the Epi study.
Epi significantly increased baseline plasma glucose concentration
(83 ± 10 vs. 98 ± 12 mg/dl, P < 0.05), whereas
it had no effect on baseline insulin [9 ± 3 vs. 11 ± 3 µU/ml, not significant (NS)] and C-peptide (1.4 ± 0.3 vs.
1.5 ± 0.3 ng/ml, NS) concentrations. As shown in Fig.
1, during the stable-label IVGTT, plasma
glucose, tracer glucose, and insulin concentrations were significantly higher in the Epi study.

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Fig. 1.
Concentration vs. time profiles of total glucose,
insulin, and tracer glucose. , Control data;
, data obtained during epinephrine (Epi) infusion.
|
|
Glucose disposal indexes.
The average trend for the derived parameters of the 2CMM showed a
decrease in magnitude for EGPb, S
, and
S
, with a significant (P < 0.05)
reduction in PCR in the Epi compared with the basal state (Table
1). Note that the reduction of
S
, albeit substantial, was not significant; the two
indexes of plasma clearance rate and glucose effectiveness were merged
into one, S
, in the one-compartment minimal model
used in our previous study (2).
EGP and plasma clearance time courses.
The administration of Epi has a striking effect on EGP profiles (Fig.
2): the nadir of the EGP profiles (Table
2) occurs at 21 ± 7 min in the
basal state and at 55 ± 13 min in the Epi state (P < 0.05).The time-varying profile of plasma clearance rate
PCR(t) was calculated from Eq. 7 and is reported
in Fig. 3: elevated Epi concentrations
seem to be associated with a substantial decrease in the glucose
clearance rate.

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Fig. 2.
Average time course of endogenous glucose production.
Values are means ± SE (n = 6) for control (thin line)
and Epi (thick line) states.
|
|

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Fig. 3.
Average time course of plasma glucose clearance rate
(PCR) calculated from model predictions in control ( )
and Epi ( ) states. Values are means ± SE
(n = 6).
|
|
 |
DISCUSSION |
The labeled IVGTT interpreted with the 2CMM allowed us to obtain
accurate and precise estimates of glucose metabolism at both peripheral
and liver levels; this is particularly important because Epi deeply
affects both glucose uptake and its hepatic release. The present data
show that exogenously increased Epi concentration not only reduced the
peripheral clearance of glucose but also had a profound effect on the EGP.
In the presence of elevated Epi levels, and with comparable baseline
EGP, we observed a significant time delay in the ability of secreted
insulin to exert its inhibitory action on glucose release after the
glucose load. This time-dependent effect is transient, and after 2 h it has completely vanished. As is apparent from Fig. 2, the time
required in the presence of Epi to have the same inhibitory action of
insulin on EGP with respect to the control study is more than double.
Interestingly, the maximal inhibitory effect of insulin is not reduced;
this means that, in terms of insulin action on glucose release, Epi
mainly reduced the ability of liver to "sense" the inhibitory
action of insulin. These results would contradict previous studies
showing that, in the presence of Epi, EGP is significantly less
inhibited by insulin (10, 23), ten- and twofold, without
and with Epi, respectively. However, such data were obtained by use of
different experimental protocols, such as the isoglycemic
hyperinsulinemic glucose clamp and glucose infusion, which may itself
alter the circulating plasma level of catecholamines (12).
This altered EGP suppression during Epi infusion was observed in the
presence of different insulin levels; therefore, we cannot tell whether the degree of suppression would be similar or less pronounced in the
Epi group if the two treatment groups had similar insulin levels.
Further studies will be needed to clarify this issue.
The following items should also be considered. Previous literature
findings have shown that increased Epi levels oppose insulin action in
modulating the endogenous rate of appearance of glucose (25). This hormone induces an initial rise in glucose
production that is largely due to the activation of glycogenolysis;
after the waning of this initial effect, Epi stimulates
gluconeogenesis, which thus becomes the major factor in maintaining
glucose production. Cherrington and colleagues [see Frizzell et al.
(11) and Stevenson et al. (26)] have shown
that the effect of Epi on glucose production lasts ~30 min.
Some hypotheses can be put forward for this waning effect of Epi on
glucose production. One is related to a possible regulatory mechanism
mediated by
-adrenergic receptors; however, it has been shown that,
in the presence of physiological levels of hyperinsulinemia, at least
in dogs, the recovery of glucose rate of appearance is not dependent on
adrenergic mechanisms (29, 33). This may suggest the
presence of an autoregulatory mechanism within the liver that may limit
the hyperglycemic effect of Epi; this hypothesis is supported by
previous studies showing that glucose autoregulates its own production
or utilization by modulating the glycogen and glycolytic pathways
(9, 28). Another possibility is the role of insulin in
limiting the Epi response. As shown in Fig. 1, Epi infusion is
paralleled by higher insulin levels determined both by the induction of
insulin resistance and by a true higher secretion when the
-cell is
challenged with a glucose load. This opposing effect of insulin on Epi
metabolic effects is not limited to glucose but is also true for lipid
metabolism (3). As far as insulin secretion is concerned,
baseline and C-peptide levels were not significantly increased despite
increased plasma glucose concentration; this confirms a basal
inhibitory effect of Epi on insulin secretion and underscores the role
of the limitation of insulin secretion in the hyperglycemic action of
this hormone (5). This effect may be one of the
determinants of the initially delayed suppression of EGP and of
subsequent glucose intolerance during Epi infusion.
Although the labeled IVGTT provides meaningful indexes of insulin
action and glucose metabolism, it does not provide figures on
splanchnic glucose uptake. This parameter may play a possible role in
our findings. Saccà et al. (22) found that Epi
infusion decreases the uptake of glucose in the splanchnic bed, which
is a pathway of glucose disposition that is relatively insensitive to
insulin. They found that splanchnic glucose uptake significantly increased from baseline after 30 min from the beginning of glucose infusion, and that during Epi challenge there is a complete blunting of
this process. Therefore splanchnic glucose uptake might hypothetically have a role in modulating EGP during Epi challenge.
Although we did not assess their concentrations, Epi infusion markedly
increases free fatty acid levels. This action may explain our findings,
because, during the IVGTT, their level drops to their nadir usually
after 50-60 min from the bolus glucose administration (27). In normal subjects, the hyperglycemic action of Epi
is enhanced by the simultaneous elevations of glucagon and cortisol (25); the former increases the magnitude, but not the
duration, of the rise in hepatic glucose output induced by Epi. It is
likely that the different time-dependent inhibitory effects of insulin in the presence of elevated Epi levels may be partly determined by
increased glucagon concentration, although we did not measure its
concentration. Another potential confounder that deserves comment is
the possible role of norepinephrine (NE), which can be elevated by Epi
and glucose infusions (8). The simultaneous increase of NE
could at least partly explain the decreased glucose clearance and the
delayed suppression of EGP (17).
As was shown in our previous study, elevated Epi concentrations
also have profound effects on glucose uptake (2). In Fig. 3, we provide strong, temporal evidence for this effect. Together with this marked effect on glucose clearance rate, we have found that
Epi decreases, although not significantly, S
and
S
, the insulin action and glucose
effectiveness indexes, respectively. The observed differences between
this and our previous study (where insulin sensitivity was
significantly decreased) may be ascribed to the different indexes
provided by the 2CMM of glucose kinetics (compared with the
one-compartment model used in our previous study) or to the relatively
low discriminating power of this study due to the small number of
subjects included. The former takes into account the fact that glucose
kinetics is described by a two-compartment model (as opposed to a
one-compartment model) and attempts to take into account the inhibitory
effect of glucose on its own clearance (see Eq. 4). Also,
insulin sensitivity and the other indexes are more difficult to
estimate with the 2CMM (which is to be expected, as the model is more
complex); however, the glucose impulse response provided by the 2CMM is needed for evaluating the time course of EGP (1). It is
worth noting that this approach has been used to assess an insulin
sensitivity index in other pathophysiological states such as type 2 diabetes (18).
In conclusion, we have shown by using a two-compartment model of
glucose kinetics that elevated plasma Epi concentrations have profound
effects at both hepatic and tissue levels; these two sites of action
can be dissected with the labeled IVGTT approach. In particular, at the
liver site, this hormone deeply affects, in a time-dependent fashion,
the inhibitory effect of insulin on glucose release. Our findings
demonstrate the complexity of hepatic glucose metabolism when human
subjects are exposed to catecholamine levels such as those observed
during physiological stress.
 |
ACKNOWLEDGEMENTS |
This work has been supported by a Grant of Regione Veneto (Progetto
Finalizzato Invecchiamento) and by National Institutes of Health Grant
P41 RR-12609 ("Resource Facility for Population Kinetics").
Preliminary results of this work were presented at the 59th Scientific
Sessions of the American Diabetes Association in San Diego, CA (June
1999) and were published as Abstract no. 1257 in Diabetes,
volume 48, Suppl 1: A288, 1999.
 |
FOOTNOTES |
Address for reprint requests and other correspondence: A. Avogaro, Cattedra di Malattie del Metabolismo, Via Giustiniani 2, 35128 Padua, Italy (E-mail:
angelo.avogaro{at}unipd.it).
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.
10.1152/ajpendo.00530.2001
Received 26 November 2001; accepted in final form 11 March 2002.
 |
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