1 Metabolism Unit, Consiglio Nazionale delle Ricerche Institute of Clinical Physiology and Department of Internal Medicine, University of Pisa, 56100 Pisa, Italy; and 2 Synthélabo Recherche, 92220 Bagneux, France
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ABSTRACT |
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We tested whether
acute 2-blockade affects
insulin secretion, glucose and fat metabolism, thermogenesis, and
hemodynamics in humans. During a 5-h epinephrine infusion (50 ng · min
1 · kg
1)
in five volunteers, deriglidole, a selective
2-receptor inhibitor, led to a
more sustained rise in plasma insulin and C-peptide levels (+59 ± 14 vs. +28 ± 6, and +273 ± 18 vs. +53 ± 14 pM,
P < 0.01 vs. placebo) despite a
smaller rise in plasma glucose (+0.90 ± 0.4 vs. +1.5 ± 0.3 mM,
P < 0.01). Another 10 subjects were
studied in the postabsorptive state and during a 4-h hyperglycemic (+4 mM) clamp, coupled with the ingestion of 75 g of glucose at 2 h. In the
postabsorptive state, hepatic glucose production, resting energy
expenditure, and plasma insulin, free fatty acid (FFA), and potassium
concentrations were not affected by acute
2-blockade. Hyperglycemia
elicited a biphasic rise in plasma insulin (to a peak of 140 ± 24 pM), C-peptide levels (1,520 ± 344 pM), and insulin secretion (to
410 ± 22 pmol/min); superimposed glucose ingestion elicited a
further twofold rise in insulin and C-peptide levels, and insulin
secretion. However,
2-blockade
failed to change these secretory responses. Fasting blood
-hydroxybutyrate and glycerol and plasma FFA and potassium
concentrations all declined with hyperglycemia; time course and extent
of these changes were not affected by
2-blockade. Resting energy
expenditure (+25 vs. +16%, P < 0.01) and external cardiac work (+28% vs. +19%,
P < 0.01) showed larger increments
after
2-blockade. We conclude
that acute
2-blockade in humans
1) prevents epinephrine-induced
inhibition of insulin secretion, 2)
does not potentiate basal or intravenous- or oral glucose-induced
insulin release, 3) enhances
thermogenesis, and 4) increases
cardiac work.
2-adrenoceptors; thermogenesis
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INTRODUCTION |
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ANIMAL AND IN VITRO STUDIES have provided clear
evidence that postsynaptic
2-adrenoceptors are present on
pancreatic
-cells (30) and that their selective stimulation inhibits
glucose-induced insulin release (17). In humans, the pioneer studies of
Robertson and Porte (28) showed that in the postabsorptive state
phentolamine, an
-receptor antagonist, increased while propranolol,
a nonselective
-blocker, inhibited insulin release. In addition,
phentolamine potentiated and propranolol depressed insulin release in
response to epinephrine-induced hyperglycemia. Normal subjects and
particularly diabetic patients were found to have improved insulin
secretion in response to intravenous glucose pulses when
-adrenoceptors were blocked with phentolamine (27). Since then, the
experimental work in this area in humans has been limited and
controversial. Basal insulin secretion and the insulin response to
arginine under hyperglycemic conditions were found to be enhanced by
-blockade in diabetic but not in nondiabetic individuals (24). In
contrast, selective
2-blockade
with midaglizole in healthy humans was found to lower both fasting
plasma glucose and the glucose response to a mixed meal, although the
effect on peripheral insulin concentrations was negligible (15). More
recently, the role of
2-adrenergic tone on insulin
secretion has been reported to be null (25) or limited to maximal
secretory capacity (24). In the aggregate, it is still unclear whether
a physiologically relevant
2-receptor tone is present in
human
-cells in the postabsorptive state, nor is it clear whether
this adrenergic tone is modulated by hyperglycemia.
The interactions of the sympathetic nervous system with glucose
metabolism in humans are complex. Insulin sensitivity and glucose-induced thermogenesis are only marginally (~15%) reduced by
acute -receptor blockade, whereas acute
-blockade with
phentolamine is without effect on either (9). In postabsorptive humans, exogenous epinephrine (a potent
- and
-agonist) infusion causes hyperglycemia through both increased hepatic glucose production and
reduced glucose clearance. The former action is transient and biphasic
(i.e., an initial acceleration of liver glycogenolysis is followed by
enhanced gluconeogenesis) and is entirely explained by liver
-adrenoceptor stimulation (32). The reduced glucose clearance is
secondary to the limitation of insulin secretion but also to a
peripheral effect, which is limited to the insulin-dependent pathways
(18) (noninsulin-mediated glucose uptake being unaffected; Ref. 4), and
is probably mediated by
2-receptors (19). Information on the effect of norepinephrine (whose action is mediated mainly by
-receptors) in humans is scarce. In the fasting state,
norepinephrine infusion, reproducing circulating levels similar to
those attained during moderate stress, produces a transient stimulation
of hepatic glucose output without altering fasting glucose clearance
(31). In the insulinized state, norepinephrine appears to reduce
glucose tolerance and insulin-stimulated glucose uptake leaving insulin secretion unaltered (21). In contrast to this finding, more recent (3)
studies have shown that norepinephrine infusion increases both basal
and insulin-mediated whole body glucose uptake. The interplay between
insulin action and the adrenergic system is further complicated by the
observation that glucose ingestion as well as exogenous insulin
infusion activates the sympathetic nervous system (particularly
noradrenergic arm; Refs. 5, 29), establishing a physiological feedback
system.
Although the relevance of all these interactions is clear under stress
conditions, when the sympathetic nervous system is strongly activated,
it is not known whether
2-adrenoceptor activity interferes with thermogenesis or glucose and/or fat metabolism under more physiological conditions. The aim of the present study was
to test in healthy subjects the effects of a selective removal of
2-receptor tone (using
deriglidole, a selective
2-blocker) on insulin
secretion, glucose utilization, energy expenditure, and hemodynamics in
the postabsorptive as well as the insulinized state. Because the
efficacy of deriglidole has been directly tested only in in vitro and
animal studies, we carried out a preliminary series of studies to
verify that the drug, at the dosage we planned to use, reaches
2-adrenoceptors on pancreatic
-cell and prevents the inhibitory action of epinephrine on insulin
secretion.
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METHODS |
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Subjects
Informed written consent was obtained from 15 healthy male volunteers aged 20-32 yr. All subjects were within 10% of their ideal body weight and had a body mass index (BMI) ranging between 22 and 25 kg/m2. None of them had a positive family history of diabetes mellitus or essential hypertension. Before entering the study, each subject completed an extensive clinical workup (history, physical examination, blood chemistry, urinalysis, and electrocardiogram) to exclude concomitant diseases or diet and/or drug treatment. All subjects were requested to maintain their habitual life style and diet for the duration of the study and to avoid strenuous physical exercise on the day before each test.Experimental Protocol
Each subject was studied twice, 1 wk apart. After a double-blind design, subjects were randomly assigned either to the active treatment [deriglidole: (+)-2-(4,5-dihydro-1H-imidazol-2-yl) 1,2,4,5-tetrahydro-2-propylpyrrolo[3,2,1-hi]-indole hydrochloride, manufactured by Synthélabo Recherche Laboratories, Paris, France] or placebo. Subjects were admitted as outpatients to the Metabolic Unit between 7:00 and 8:00 AM after an overnight fast (11-12 h). For the entire duration of the study, the subjects rested supine in a quiet, air-conditioned room. An antecubital vein (for infusion of test substances) and a wrist vein (for blood sampling) were cannulated, and the hand was then inserted into a heated box (70°C) to achieve arterialization of venous blood.Study 1.
Five subjects participated in the study. Thirty minutes after catheter
placement, a 30-min baseline period started during which blood samples
were obtained for substrate [glucose, glycerol, free fatty acids
(FFA)] and hormone (plasma glucose, insulin, and C-peptide)
determination. At 0 min, epinephrine (ISM, Milan, Italy) was infused at
a constant rate (50 ng · min1 · kg
1)
for the following 300 min. Twice during the study, at 0 and 180 min,
subjects ingested a tablet of either deriglidole (15 mg) or placebo.
Blood pressure and heart rate were measured hourly. Blood samples for
glucose determination were obtained every 10 min for the 1st h and
every 30 min thereafter. Plasma insulin, FFA, and potassium were
determined at 30-min intervals.
Study 2.
After catheter placement, subjects (n = 10) were asked to void, and thereafter a primed (30 µCi) constant
(0.27 µCi/min) infusion of
[3-3H]glucose (NEN,
Boston, MA) was started and continued for 3 h (from 120 min to
60 min). At
60 min, the subject's head was placed in a
ventilated Plexiglas hood, and gas exchange was measured by using a
computerized, continuous, open-circuit system (Metabolic Measurement
Cart Horizon, Sensor Medics, Anaheim, CA). Twice during the study, at 0 and 180 min, subjects ingested a tablet of either deriglidole (15 mg)
or placebo. Three baseline blood samples (at
10,
5, and 0 min) were collected for the determination of plasma C-peptide, insulin,
FFA, potassium, and glucose specific activity. The same assays were
done on subsequent blood samples taken at 10-min intervals until 60 min. At this time, the
[3-3H]glucose infusion
was stopped, the subjects voided, and a hyperglycemic clamp (raising
plasma glucose 4.0 mM above fasting value) was then started following
the method of DeFronzo et al. (10). Plasma glucose was measured every 5 min, and the frequency of blood sampling for plasma insulin and
C-peptide was as depicted in the Fig. 3. At 180 min (after 2 h of
hyperglycemia), urine was again collected; subjects then drank 150 ml
of a 50% glucose-in-water solution and ingested a second tablet (15 mg
of deriglidole or placebo). For the following 2 h (until 300 min),
plasma glucose was maintained at +4.0 mM above baseline by modifying
the exogenous glucose infusion rate according to the observed plasma
glucose changes. Plasma FFA and potassium, blood
-hydroxybutyrate,
and glycerol were measured every 30 min throughout. A third urinary
collection was made at the end of the study. Gas exchange was also
measured during the last 60 min of the hyperglycemic clamp
(120-180 min) and the final 60 min after glucose ingestion
(240-300 min). Arterial blood pressure, with a standard mercury
sphygmomanometer, and heart rate were measured every 20 min.
Analytical Procedures
Plasma glucose was assayed by the glucose oxidase method (Glucose Analyzer, Beckman Instruments, Fullerton, CA). Plasma potassium was assayed in duplicate immediately after blood drawing by an ion-selective electrode method (Microlytes 6 Selective Ion Analyser, Kone Instruments, Espoo, Finland). Plasma FFA were determined by an enzymatic method (Wako Chemical, Neuss, Germany). For determination of glycerol andData Analysis
Glucose utilization (M) values were calculated according to DeFronzo et al. (10). Protein oxidation was estimated from the nonprotein urinary nitrogen excretion rate over the three collection periods ( ![]() |
RESULTS |
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Study 1
Basal plasma epinephrine (average ofAt baseline, plasma glucose, insulin, and C-peptide concentrations were similar in the two experiments (Fig. 1). In the placebo study, plasma glucose gradually rose and reached a plateau at 1 h that was maintained for the following 4 h. This prolonged hyperglycemia induced only a minor increase in plasma insulin levels, averaging +28 ± 6 pM over 300 min. Deriglidole administration was associated with a blunted and more transient rise in plasma glucose levels (P < 0.05 by ANOVA for treatment and time × treatment effect), which returned to baseline at the end of the study (Fig. 1). This glycemic excursion was associated with plasma insulin levels that were twice as high as in the placebo study (P < 0.05 by ANOVA). When the efficiency of insulin secretion was estimated as the ratio of the incremental (above baseline) insulin area to the incremental glucose area, deriglidole was associated with an eightfold increase in insulin release compared with placebo (116 ± 44 vs. 15 ± 2 pmol/mmol, P < 0.02 by paired t-test). Over 300 min, the excess of insulin secreted in response to deriglidole (as calculated by deconvolution analysis of plasma C-peptide) averaged 13.5 ± 3.6 nmol (1.9 ± 0.5 U). Fasting plasma FFA levels were similar in the two studies (Fig. 2). With placebo, the infusion of epinephrine elicited a sharp 150% rise of plasma FFA, followed by a rapid decline to values still 50% above baseline for the remaining 200 min. Deriglidole administration did not prevent the early rise but was associated with a greater decline of plasma FFA, which returned to baseline levels at 120 min (P < 0.01 by ANOVA for interaction time × treatment). As shown in Fig. 2, plasma potassium declined in response to epinephrine infusion, and the gradient tended to be more pronounced after deriglidole administration (P = 0.08 by ANOVA).
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Study 2
Deriglidole. Plasma deriglidole concentrations reached 7.1 ± 2.5 ng/ml 60 min after the first capsule ingestion and averaged 6.5 ± 1.4 ng/ml at 180 min, immediately before the second capsule was ingested. A further rise, to 11.2 ± 4.2 ng/ml, was observed at 300 min (2 h after ingestion of 2nd capsule). In both series of studies, no deriglidole was detectable in plasma at baseline and after placebo.
Glucose, insulin, and C-peptide.
The time course of glucose, insulin, and C-peptide concentrations is
shown in Fig. 3. Basal plasma glucose was
superimposable on the occasion of the two studies and did not change
during the 60 min after either deriglidole or placebo ingestion. During
the hyperglycemic clamp, plasma glucose reached a stable level within 40 min of glucose infusion. The mean increment during the 2nd h of the
clamp was 3.8 ± 0.1 mM in the placebo study and 3.7 ± 0.1 mM in
the active drug study (P = NS by
paired t-test). After glucose
ingestion at 180 min, plasma glucose was maintained relatively stable
on both occasions, the intraindividual mean coefficients of variation
for the entire hyperglycemic period being 6.8 ± 0.8% and 6.9 ± 0.9% (control vs. 2-blockade).
No statistically significant difference in plasma glucose between
treatment and placebo was observed in any period of the study
(P = NS).
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Metabolites.
Baseline plasma FFA (0.443 ± 0.036 vs. 0.478 ± 0.069 mM,
placebo vs. treatment), blood -hydroxybutyrate (0.107 ± 0.020 vs. 0.162 ± 0.046 mM), and glycerol (0.042 ± 0.007 vs. 0.055 ± 0.008 mM) concentrations were similar on the two
occasions and did not change during the 60 min after ingestion of the
first capsule. Hyperglycemia produced a marked decrease in plasma FFA,
blood
-hydroxybutyrate, and glycerol concentrations (to nadirs of
0.083 ± 0.013, 0.020 ± 0.003, and 0.019 ± 0.005 mM,
respectively). These metabolites showed similar profiles during the
treatment and placebo study.
Potassium. Baseline plasma potassium levels (3.93 ± 0.05 vs. 3.93 ± 0.05 mM) were superimposable in the two studies, were unchanged after the first capsule, and showed a similar 10% decline during the hyperglycemic clamp (to 3.67 ± 0.06 vs. 3.66 ± 0.05 mM, placebo vs. treatment, respectively); a further 4% decline (to 3.55 ± 0.06 vs. 3.50 ± 0.06 mM, respectively) was observed after glucose ingestion similarly in the deriglidole and placebo studies.
Glucose disposal.
Basal plasma
[3H]glucose specific
activities had a mean coefficient of variation of 3.4 ± 0.4% and
averaged 3,894 ± 407 cpm/mg in the placebo study and 4,231 ± 276 cpm/mg in the deriglidole study (P = NS). The calculated glucose Ra
values were 11.5 ± 0.4 and 11.1 ± 0.4 µmol · min1 · kg
1.
Ingestion of the first capsule was associated with no significant changes from baseline in plasma
[3H]glucose specific
activity in either study. Furthermore, when all the data of the
10- to 60-min period were analyzed with the two-compartment
model (22), no significant changes in glucose Ra from baseline were observed in
either set of experiments. During the hyperglycemic clamp, the mean
glucose infusion rate plateaued at ~30
µmol · min
1 · kg
1
between 160 and 180 min, remained at this level for an additional ~60
min despite oral glucose administration, and further rose to ~60
µmol · min
1 · kg
1
during the final hour (P < 0.01 by
ANOVA). The M values (i.e., mean glucose infusion rate corrected for
concomitant changes in body glucose pool) were slightly (12%) higher
with
2-blockade than with
placebo (P = 0.01 for time × treatment interaction by ANOVA).
Gas exchange and indirect calorimetry.
Gas exchange and indirect calorimetry values are given in Table
1. Baseline
O2 and
CO2 were similar in the two
sets of experiments and were not affected by the first capsule
(0-60 min). During intravenous glucose alone, both
O2 and
CO2 increased slightly,
though not significantly. In contrast, glucose ingestion was followed
by a 13% rise in
O2 and a
34% increase in
CO2 (P < 0.01 for both), so that the
calculated respiratory quotient (RQ) increased to values very close to
1.
2-Blockade resulted in
higher increments in both
O2
(+20%) and
CO2 (+43%)
(P < 0.01 for both treatment effects
by ANOVA) and a similar increase in RQ. Carbohydrate oxidation was
significantly stimulated and lipid oxidation suppressed during
hyperglycemia, but there was no systematic difference between
2-blockade and placebo. On the other hand, glucose ingestion was associated with a marked stimulation in thermogenesis (i.e., a 16% increase in energy expenditure, P < 0.01), which was significantly
enhanced (+25%, P < 0.01 vs. placebo) by
2-blockade.
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Hemodynamics.
During the placebo study, systolic and diastolic blood pressure and
heart rate remained unchanged until 60 min (Fig.
4). Subsequently, there was a gradual
increase in both systolic blood pressure and heart rate
(P < 0.01 for time effect by ANOVA),
whereas diastolic blood pressure fell by 5%
(P < 0.01). These changes account
for the 18% increase from basal values in the double product (systolic blood pressure × heart rate; 7,127 ± 337 vs. 8,527 ± 386 mmHg · beats1 · min
1,
P < 0.01 by paired
t-test) at the end of the study.
2-Blockade was associated with
greater increments in blood pressure, heart rate, and double product,
which reached statistical significance for both diastolic and double
product (P < 0.01 for time × treatment interaction by ANOVA).
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DISCUSSION |
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Deriglidole is a peripheral adrenoceptor antagonist with a high
affinity for 2-adrenoceptors.
It inhibits
[3H]clonidine and
[3H]idazoxan but not
[3H]prazosin binding
to rat cortical and human platelet
2-adrenoceptors and is more
selective than idazoxan for peripheral receptors (1). Because its
2-antagonistic activity on
pancreatic adrenergic receptors in humans has not been previously
assessed, we carried out preliminary experiments to document the
ability of deriglidole to prevent the inhibitory effect of epinephrine
specifically on insulin secretion. Our results of
study 1 confirm that epinephrine infusion, at doses that raise plasma epinephrine to levels typically encountered during severe stress, causes stable hyperglycemia, which is
known to result from transient stimulation of hepatic glucose
production, reduction of peripheral glucose clearance, and restraint of
insulin secretion. Although the first two actions are mediated by
2-adrenoceptors (19), the
latter is largely dependent on
2-receptor activation (26). The
time course of plasma glucose, insulin, C-peptide, and insulin
secretion rate during these experiments (Fig. 1) unequivocally
indicates that insulin secretion was improved by deriglidole
administration. Furthermore, the relative hyperinsulinemia observed
during
2-blockade (+30 pM),
though small in absolute terms, was enough to counteract also the
lipolytic activity of epinephrine (Fig. 2), confirming the exquisite
sensitivity of lipolysis to minor changes in insulin levels in normal
subjects. In addition, deriglidole prevented the epinephrine-induced
inhibition of insulin secretion despite the associated (and expected;
Refs. 6, 24) increase in plasma norepinephrine concentrations, which
per se might have enhanced the
2-inhibitory tone on
-cells.
Whether the effect of deriglidole on insulin secretion is solely
determined by the removal of excess
2-receptor tone or is also
dependent on a direct activation of ATP-dependent potassium channels
through a class-specific (imidazoline) receptor (16, 30), as suggested
by preliminary evidence (14), is not known. The latter possibility,
however, is not supported by the results of the current
study 2 experiments, in which
deriglidole alone (i.e., in absence of excess epinephrine) was without
effect on insulin secretion.
The second series of experiments was designed to determine the effects
of acute 2-blockade on basal
insulin secretion (0-60 min), glucose-induced insulin secretion
(60-180 min), and gastrointestinal potentiation of glucose-induced
insulin secretion (180-300 min). Although stimulated insulin
secretion is closely reflected in circulating insulin levels, inferring
changes in basal insulin secretion from measurements of peripheral
plasma insulin concentrations may be insufficiently sensitive. Minor
changes in portal insulin concentrations that are sufficient to exert
metabolic actions on the liver may not be associated with detectable
changes in the systemic hormone concentrations. In addition, the
half-maximal effective dose of insulin for some peripheral actions
(e.g., inhibition of lypolysis and stimulation of potassium uptake;
Ref. 34) is in the range 60-120 pM, i.e., not too far outside the
error boundary of fasting insulin levels. In addition to measuring
insulin secretion (by deconvolution analysis of C-peptide), we used
hepatic glucose production, plasma FFA, blood glycerol,
-hydroxybutyrate, and plasma potassium measurements as multiple
tracings for changes in insulin secretion. The observation that none of
these parameters showed any significant differences between placebo and
deriglidole for 60 min after drug administration led us to the
conclusion that, in healthy individuals, neither basal insulin
secretion nor lipolysis are affected by acute
2-blockade. Thus, in the postabsorptive state,
-cells do not appear to be under tonic adrenergic inhibition, in agreement with previous work in rats (13) and
in contrast to recent experimental work in dogs (12) and the finding of
Robertson and Porte (28). The latter study was done in six subjects
with a wide weight range (from 91 to 133%) of ideal body weight, and
phentolamine infusion was associated with a very small rise in plasma
insulin (from 10 to 12 µU/ml). We cannot exclude that our study
design may have missed such a small change or, alternatively, that
2-blockade might have been more
effective on basal insulin secretion in subgroups of subjects (as
suggested by greater insulin changes observed in those with higher
fasting plasma insulin levels). In addition, the discrepancy might
depend on the lack of specificity of phentolamine for
2-adrenoceptors. More recently,
it has been reported that, in conscious dogs, the ingestion of
deriglidole results in a prompt (within 30 min) increase in plasma
insulin and FFA concentrations (12). The higher dose used (1 mg/kg) or
species differences might explain these discrepancies. Obviously, our
conclusions are limited to the time frame and dosage used here.
However, the plasma deriglidole concentrations already measured after
60 min and throughout the study are within the half-maximal inhibitory
concentration (1 ng/ml) for the in vitro inhibition of selective
agonist binding to
2-receptors.
We cannot exclude that higher doses may have an effect on basal insulin secretion via a sulfonylurea-like mechanism on ATP-sensitive potassium channels, as recently demonstrated in mouse islets (14). According to
the latter data, we calculated that, if the plasma concentration achieved in the present study were reproduced in vitro, a mouse islet
preparation would respond with a 10-15% greater insulin secretion
to a 15 mM glucose challenge.
With regard to glucose-stimulated insulin secretion, our protocol reproduced both the biphasic insulin release that follows acute intravenous glucose administration and the potentiation of glucose-induced insulin secretion that is elicited by glucose ingestion (8). Of interest is that, although the previous study (8) has used +7 mM hyperglycemia to document gastrointestinal potentiation of insulin secretion, the current results show that this phenomenon is already evident with more physiological plasma glucose elevations.
Acute hyperinsulinemia obtained by means of intravenous glucose
infusion as well as glucose ingestion (5, 29) is known to be associated
with an activation of the adrenergic nervous system. One consequence of
such activation could be limitation of glucose-induced insulin
secretion, i.e., a negative-feedback loop on the -cell. However, in
the current experiments despite boosting
2-blockade with another dose of
deriglidole, we were unable to detect any enhancement (or derepression)
of pancreatic
-cells during either intravenous or intravenous plus
oral glucose administration.
Under conditions of stable hyperglycemia, the exogenous glucose
infusion rate equals total glucose disposal (i.e., M) provided that
hepatic glucose production is completely suppressed. Although we did
not measure hepatic glucose output during the glucose clamp, it may be
safely assumed that the combination of portal hyperinsulinemia and
hyperglycemia caused full inhibition of endogenous glucose production
in our normal volunteers. Glucose metabolism increased during
intravenous glucose administration and was further stimulated as
endogenous insulin release was potentiated by oral glucose (Table 1,
Fig. 3). After glucose ingestion, the calculated M value underestimates
the total rate of glucose utilization by an amount equal to oral
glucose absorption. 2-Blockade
was associated with a small (12%) increase in M through the whole
hyperglycemic period, which persisted when only the 60- to 180-min time
block (intravenous glucose alone) was analyzed. Thus
2-blockade appears to have a
favorable, if small, influence on peripheral glucose uptake.
During the final hour of the control study, energy expenditure was 16%
higher than at baseline. This thermogenic response, which is twice as
high as that observed under conditions of euglycemic hyperinsulinemia
(11), is the combined result of a stronger stimulation of glucose
disposal and gastrointestinal glucose processing. 2-Blockade was associated with
a significantly higher thermogenic response (Table 1). The mechanism of
this effect can be surmised by considering that, under euglycemic
conditions, the thermogenic response to insulin is decreased by
propranolol (a nonselective
-blocker) but not by a nonselective
-blocker (phentolamine) (9). Probably, blockade of presynaptic
2-inhibitory adrenoceptors, by
favoring catecholamine release (20), provided an additional drive for
-activity. The biochemical basis of the observed enhancement of
energy expenditure by
2-blockade cannot be determined
from our data but is likely to be due to acceleration of futile
metabolic cycles as occurs during stress (23).
In the control experiments, a marked hyperdynamic response to
hyperglycemia was observed (Fig. 4), with the double product increasing
linearly up to 20% above baseline. This is compatible with a systemic
adrenergic activation resulting in an increase in heart rate, a fall in
diastolic blood pressure, and a rise in systolic blood pressure, a
response qualitatively similar to that observed during the epinephrine
infusion (study 1). However, we
cannot rule out a direct vasodilatory effect of insulin, although this
effect is usually observed at higher insulin concentrations (2). Acute
2-blockade caused a further
increase in heart rate and systolic blood pressure and abolished the
fall in diastolic blood pressure (Fig. 4). The mechanism presumably is
consistent with the removal of the prejunctional
2-mediated inhibition of norepinephrine release (20). It is here worth recalling that clonidine,
a potent
2-agonist, when
parenterally administred, after a transient (1-2 min) rise in
blood pressure due to vascular postjunctional
2-receptor stimulation, induces
prolonged and stable hypotension. Because neither blood flow nor muscle
sympathetic nerve activity were measured in our study, we cannot
exclude the possibility that
2-receptor blockade caused
sympathetic activation via a hemodynamic reflex; the higher diastolic
blood pressure values associated with
2-blockade (Fig. 4), however,
argue against this mechanism.
In conclusion, in normal subjects, acute selective
2-blockade prevents
epinephrine-mediated inhibition of insulin secretion but does not
potentiate either basal or glucose-induced (intravenous or oral)
insulin release. It causes a mild increase in blood pressure and a
marked enhancement of thermogenesis. These effects are probably related
to a shift in the adrenergic balance toward
- and
1-activity.
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ACKNOWLEDGEMENTS |
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This study was funded in part by Synthélabo Recherche, Milano.
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FOOTNOTES |
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Address for reprint requests: A. Natali, CNR Institute of Clinical Physiology, Via Savi, 8, 56100 Pisa, Italy.
Received 22 April 1997; accepted in final form 16 September 1997.
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