Laboratory of Experimental Medicine, Brussels Free University, B-1070 Brussels, Belgium
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ABSTRACT |
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Isolated perfused rat pancreases were exposed,
in the presence of 10.0 mM
L-leucine, to either
-D-glucose pentaacetate,
-L-glucose pentaacetate, or
unesterified D-glucose, all
tested at a 1.7 mM concentration. The pentaacetate ester of
-D-glucose and, to a lesser
extent, that of
-L-glucose
stimulated both insulin and somatostatin release, whereas unesterified
D-glucose failed to do so. In
the case of insulin output, the two esters differed from one another
not solely by the magnitude of the secretory response but also by its
time course and reversibility. Compared with these data, the most
salient difference found in the case of somatostatin release consisted
of the absence of an early secretory peak in response to
-D-glucose pentaacetate
administration and the higher paired ratio between the secretory
responses evoked by the esters of glucose and by unesterified
D-glucose (5.5 mM) administered
at the end of the experiments. The two esters provoked an initial and
short-lived stimulation of glucagon secretion, in sharp contrast to the
immediate inhibitory action of unesterified D-glucose. Thereafter,
-D-glucose pentaacetate, but
not
-L-glucose pentaacetate,
caused inhibition of glucagon release, such an effect being reversed
when the administration of the ester was halted. These findings
indicate a dual mode of action of glucose pentaacetate esters on
hormonal secretion from the endocrine pancreas. The intracellular
hydrolysis of
-D-glucose
pentaacetate and subsequent catabolism of its hexose moiety may
contribute to the early peak-shaped insulin response to this ester, to
the persistence of a positive secretory effect in B and D cells after
cessation of its administration, and to the late inhibition of glucagon
release. However, a direct effect of the esters
themselves, by some as-of-yet unidentified coupling process, is
postulated to account for the stimulation of insulin and somatostatin
release by
-L-glucose
pentaacetate and for the initial enhancement of glucagon secretion
provoked by both glucose esters.
insulin secretion; somatostatin secretion; glucagon secretion
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INTRODUCTION |
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SEVERAL ESTERS OF MONOSACCHARIDES were recently
introduced as tools to increase the nutritional value and/or
biological efficiency of the corresponding carbohydrates. This approach
is inspired by the consideration that the esters cross the plasma
membrane without requiring the intervention of a specific transport
system and then undergo intracellular hydrolysis, so that the sugar
moiety becomes readily available to act as a nutrient or metabolic
inhibitor (13). For instance,
-D-glucose pentaacetate is
better metabolized and displays a higher insulinotropic action than
unesterified D-glucose (18, 20).
Likewise, D-mannoheptulose
hexaacetate inhibits D-glucose
metabolism in cells otherwise resistant to the heptose (5, 15). The
tetraacetate ester of
2-deoxy-D-glucose is also more
potent than unesterified
2-deoxy-D-glucose as either an
inhibitor of D-glucose
metabolism and insulinotropic action in pancreatic islets (21) or as a
cytostatic agent in several lines of tumoral cells (2, 10, 11, 19).
Surprisingly, however, a few esters of hexoses that are either not
metabolized (e.g., -L-glucose
pentaacetate) or even inhibitors of
D-glucose metabolism (e.g.,
2-deoxy-D-glucose tetraacetate) were also found to stimulate insulin release under suitable
experimental conditions (12, 14, 18). Several findings indicate that such a situation cannot be accounted for by the metabolism of the
acetate moiety of these esters. For example,
-D-galactose pentaacetate,
which is as efficiently taken up and hydrolyzed in pancreatic islets as
-D-glucose pentaacetate (20,
22), fails to display any insulinotropic action. Moreover, the
secretory response to the latter ester is not duplicated by the
combination of unesterified
D-glucose and either acetic acid
or its methyl or ethyl esters (13, 18).
The unexpected observation that esters of hexoses devoid of nutritional value may stimulate insulin release has led to the proposal that such esters might themselves act directly on pancreatic islet B cells at the intervention of specific receptors in a manner somehow comparable to that involved in the recognition of bitter compounds by taste buds (17).
In light of these considerations, the major aim of the present study
was to search for further evidence in support of the postulated dual
mode of action of selected hexose pentaacetates on insulin release from
the endocrine pancreas. For such a purpose, the effects of
-D-glucose pentaacetate and
-L-glucose pentaacetate on
the secretion of insulin, glucagon, and somatostatin were compared with
those of unesterified D-glucose
in isolated perfused rat pancreases.
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MATERIALS AND METHODS |
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The pentaacetate esters of
-D-glucose and
-L-glucose were purchased
from Sigma Chemical (St. Louis, MO).
Fed female Wistar rats (B & K Universal, Hull, UK) were anesthetized with pentobarbital sodium, and the pancreas was perfused free from adjacent organs through both the celiac and superior mesenteric arteries, as described elsewhere (16).
The basal salt-balanced perfusion medium contained
L-leucine (10.0 mM), dextran
(clinical grade; 40 g/l), and BSA (RIA grade; 5 g/l). It also
contained, as required,
-D-glucose pentaacetate (1.7 mM),
-L-glucose pentaacetate
(1.7 mM), or unesterified
D-glucose (1.7 or 5.5 mM).
The techniques used for the measurement of plasma glucose and insulin concentrations; perfusion pressure; and pancreatic insulin, glucagon, and somatostatin content and release were identical to those mentioned elsewhere (7, 8). The concentration of D-glucose in the effluent was measured by the hexokinase/glucose-6-phosphate dehydrogenase method (1).
The oscillatory pattern of hormonal release was assessed by a procedure
previously reported (6). In each individual experiment, the mean
hormonal output over a given period of time was calculated from all
measurements made over that period. The basal hormonal output was
computed from min 20 to
min 25, inclusive. The absolute values
for such a basal output were, as a rule, not significantly different
from one another in the three series of experiments conducted with
-D-glucose pentaacetate,
-L-glucose pentaacetate, and
unesterified D-glucose, whether
in the case of insulin, somatostatin, or glucagon. The basal output of
glucagon was somewhat higher (P < 0.05), however, in the experiments with
-D-glucose pentaacetate than
with
-L-glucose pentaacetate.
Table 1 lists the characteristics of rats
and experimental variables.
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All results are presented as means ± SE together with the number of individual observations (n). The significance of differences between mean values was assessed by use of Student's t-test and ANOVA.
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RESULTS |
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In the experiments conducted with unesterified D-glucose, the concentration of the hexose in the effluent progressively increased from 0.27 ± 0.03 mM at min 28 to 1.69 ± 0.05 mM at min 34 and decreased from 1.71 ± 0.07 mM at min 53 to 0.34 ± 0.01 mM at min 58. These measurements allowed for correction for the dead space of the perfusion device. Hence, as seen in Figs. 1-6, the vertical dotted lines correspond to the time at which a change in D-glucose concentration was first detected in the effluent medium collected from the perfused pancreas.
In the experiments conducted in the presence of either
-D-glucose pentaacetate or
-L-glucose pentaacetate, no
sizable increase (<0.02 mM) in the
D-glucose concentration of the
effluent was observed in response to the administration of the ester.
The perfusion pressure was not affected by the administration of either D-glucose or its esters (data not shown).
The administration of
-D-glucose pentaacetate (1.7 mM) provoked a biphasic increase in insulin output, with slow
oscillations during the late period of exposure to the ester (Fig.
1, top). For instance, after the initial peak at min
34-35, a second secretory peak was recorded at
min 42-43, i.e., 7.5 ± 0.3 min later. After the first peak, the hormonal output reached, within
3.5 ± 0.3 min, a nadir value, which corresponded to a
66.9 ± 5.0% fractional decrease in secretory rate, whereas the
subsequent rise in insulin release after this first nadir corresponded
to a 160.9 ± 19.5% relative increment in secretory rate
(n = 4 in all cases). A third reascension in insulin output was observed after the second nadir (min 45.0 ± 0.4), the hormonal
output again increasing over 4 min by 60.3 ± 15.5% above the
paired preceding value. As computed over a period of 22 min
(min 29-50), the integrated
amount of insulin released during stimulation by the ester averaged
98.8 ± 14.2% (n = 4) of
the paired value recorded at the end of the experiments
(min 79-100) in response to the
administration of 5.5 mM unesterified
D-glucose.
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The administration of
-L-glucose pentaacetate (1.7 mM) also resulted in an increase in insulin output. However, the mean output of insulin during exposure to
-L-glucose
(min 29-53, inclusive) averaged
no more than 0.43 ± 0.05 ng/min (n = 4), as distinct (P < 0.01) from
6.98 ± 1.54 ng/min (n = 4) in the
case of
-D-glucose pentaacetate. Likewise, between min 46 and 50, the output of insulin, when
expressed relative to the paired basal value (min
20-25), averaged no more than 6.4 ± 1.9 (n = 4) during exposure to
-L-glucose pentaacetate, as
compared (P < 0.05) with 63.2 ± 21.9 (n = 4) in the case of
-D-glucose pentaacetate (Fig.
2).
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The secretory responses of the B cells to each of these two esters also
differed from one another by their time courses. Thus, whereas an early
secretory peak reaching its zenith value at min 34-35 was always recorded during stimulation by
-D-glucose pentaacetate, such
apparently was not the case in the pancreases exposed to
-L-glucose pentaacetate.
Nevertheless, in the latter experiments, the secretory rates recorded 3 min before and 3 min after the highest value found at
min 33-35 averaged, respectively,
46.8 ± 15.2 and 75.8 ± 6.6% of such a value, suggesting the
possible occurrence of a modest early phasic response.
The experiments conducted in the presence of
-D-glucose pentaacetate and
-L-glucose pentaacetate also
differed from one another by the pattern of reversibility when the
administration of the esters was interrupted at min
53. After exposure to
-L-glucose pentaacetate, the
output of insulin, whether expressed in absolute terms or relative to
basal value, rapidly declined to a level close to that found after
administration of unesterified
D-glucose. After exposure to
-D-glucose pentaacetate, a
rapid and dramatic decrease in insulin output was also observed.
Thereafter, however, an oscillatory pattern of insulin release was
recorded over the ensuing 15 min, the hormonal output remaining higher
than that found at the same time in the two other series of
experiments. Thus, between the 58th and 72nd min of perifusion, the
secretory rate averaged 0.96 ± 0.24 ng/min after exposure to
-D-glucose pentaacetate, as
distinct (P < 0.005) from only 0.34 ± 0.05 and 0.26 ± 0.09 ng/min after administration of
-L-glucose pentaacetate and
unesterified D-glucose,
respectively. Relative to paired basal value (min
20-25), these secretory rates corresponded to
mean respective values of 5.77 ± 2.46 as compared
(P < 0.10) with 3.42 ± 0.87 and
2.02 ± 0.68 (n = 4 in all cases).
In contrast to the results just mentioned, the administration of unesterified D-glucose (also 1.7 mM) failed to affect significantly insulin output. Indeed, in the presence of the unesterified hexose, the output of insulin, when expressed relative to paired basal value, averaged only 1.3 ± 0.5 (n = 4) between min 46 and 50.
The functional integrity of the perfused pancreases was assessed at the
end of the experiments by monitoring the secretory response to 5.5 mM
unesterified D-glucose. In all
cases, the hexose evoked a biphasic increase in insulin release, with
typical oscillations during the late phase of stimulation. The
functional response to the sugar appeared somewhat higher after prior
stimulation with either
-D-glucose pentaacetate or
-L-glucose pentaacetate than
after a prior administration of unesterified
D-glucose (Fig. 1). Such
differences failed, however, to achieve statistical significance, the
mean value for insulin release between min
70 and 100 averaging 6.61 ± 1.65, 4.46 ± 0.62, and 3.52 ± 0.90 ng/min
after prior exposure to
-D-glucose pentaacetate,
-L-glucose pentaacetate, and
unesterified D-glucose,
respectively.
The secretory data concerning the release of somatostatin were, in
three respects, comparable to those obtained in the case of insulin
output. Thus -D-glucose
pentaacetate and, to a lesser extent
(P < 0.005),
-L-glucose pentaacetate, but
not unesterified D-glucose,
augmented somatostatin output (Fig. 3).
Second, when the administration of the esters was interrupted at
min 53, the output of somatostatin
rapidly declined, reaching between min 58 and 72 a mean level
somewhat higher, albeit not significantly so, after exposure to
-D-glucose pentaacetate (4.6 ± 0.9 pg/min) or
-L-glucose pentaacetate (6.8 ± 3.2 pg/min) than after administration of unesterified
D-glucose (1.7 ± 0.3 pg/min). Expressed relative to paired basal value, such secretory rates
averaged, respectively, 1.31 ± 0.19 as distinct
(P < 0.001) from 0.55 ± 0.12 and
0.36 ± 0.09 (Fig. 4). Last, the mean
value for somatostatin release evoked by
D-glucose at the end of the
experiments was higher after prior exposure of the pancreas to
-D-glucose pentaacetate or
-L-glucose pentaacetate
rather than unesterified
D-glucose (Fig. 3). Such a
difference remained obvious when the release of somatostatin was
expressed relative to its paired basal value. For instance, the
secretory peak recorded at min 81 averaged, relative to paired basal output, 2.99 ± 0.49 and 2.02 ± 0.87 after prior administration of
-D-glucose pentaacetate and
-L-glucose pentaacetate,
respectively, as distinct (P < 0.05)
from only 0.83 ± 0.26 after prior exposure of the pancreas to
unesterified D-glucose.
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The secretory response to the esters largely exceeded, however, that
evoked at the end of the experiments by 5.5 mM
D-glucose, at variance with the
situation found in the case of insulin output. Another marked
difference between insulin and somatostatin output consisted of the
virtual absence of an early somatostatin secretory peak in the
pancreases exposed to
-D-glucose pentaacetate. The absence of an early stimulation of somatostatin release by the glucose
esters contrasted with the occurrence of an early secretory peak when
the pancreas was exposed to unesterified
D-glucose at the end of the
experiments. Indeed, in the latter situation, an initial peak-shaped
response was always observed, even after prior exposure to unesterified
D-glucose. Thus the output of
somatostatin at min 79 and
83, respectively, averaged, relative
to the paired value recorded at min
81, 15.5 ± 8.7 and 12.9 ± 14.2% after prior stimulation by
-D-glucose
pentaacetate, 32.4 ± 6.1 and 49.2 ± 11.7% after prior delivery
of
-L-glucose pentaacetate,
and 36.8 ± 5.1 and 34.2 ± 9.1% after prior administration of
unesterified D-glucose
(n = 4 in all cases).
Figure 5 illustrates the effects of hexose esters and unesterified D-glucose on glucagon secretion.
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The first effect of the glucose esters was to provoke a rapid but
short-lived stimulation of glucagon release. In terms of the absolute
or relative magnitude of this early increment in glucagon secretion and
its time course, there was little to distinguish between
-D-glucose pentaacetate and
-L-glucose pentaacetate. For
instance, the peak values recorded at min
30-31 were 0.78 ± 0.26 and 0.56 ± 0.22 ng/min higher than the paired reading at min
28 in the case of
-D-glucose pentaacetate and
-L-glucose pentaacetate,
respectively. Likewise, when expressed relative to the paired mean
basal value (min 20-25), the
mean output of glucagon during the early peak-shaped response
(min 29-34) averaged 103.4 ± 7.6 and 115.4 ± 14.0% in pancreases exposed to
-D-glucose pentaacetate and
-L-glucose pentaacetate,
respectively (Fig. 6).
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The early stimulation of glucagon output by the glucose esters
contrasted with an early inhibitory action of unesterified D-glucose on glucagon secretion.
Indeed, as computed over two successive periods of 7 min each, the
exponential line relating glucagon release (R) to time
(t), according to the equation R = Ro · eKt,
yielded a higher K value
(P < 0.05) after
(min 28-34) than before (min 22-28) introduction of the
hexose, with a mean paired difference of 2.45 ± 0.67 × 10
2/min
(n = 4).
The effects of -D-glucose
pentaacetate and
-L-glucose
pentaacetate on glucagon release differed vastly from one another, however, from the 35th min onward. In pancreases exposed to the ester
of L-glucose, the rate of
glucagon release resumed a value virtually identical to that calculated
by exponential extrapolation between the readings recorded at
min 28 and
63, i.e., just before administration
of the ester and 10 min after such an administration. Thus the mean
output of glucagon between the 39th and 53rd min averaged 101.2 ± 3.4% of the paired theoretical value on the basis of such an
extrapolation. In contrast, in the pancreases exposed to
-D-glucose pentaacetate, the
output of glucagon rapidly reached much lower values. As a result of
this difference, the release of glucagon during the last 15 min of
administration of the ester (min 39 to
53), when expressed relative to the
paired basal value, averaged no more than 23.8 ± 5.7% in the case
of
-D-glucose pentaacetate, as distinct (P < 0.06) from 48.5 ± 8.4% in the case of
-L-glucose pentaacetate.
Moreover, when the administration of the ester was halted and after a
transient fall in secretory rate, the output of glucagon remained
virtually unchanged after exposure to
-L-glucose pentaacetate while
progressively increasing after delivery of
-D-glucose pentaacetate. This
indicates that the late inhibitory action of the latter ester on
glucagon release was rapidly reversible. The secretory rates reached 15 min after interruption of the administration of the ester
(min 69 to
75) were indeed virtually identical
in the two series of experiments. Relative to paired basal value (min 20-25), they averaged 42.1 ± 8.3 and 42.8 ± 7.0% in the experiments involving the
administration of
-D-glucose
pentaacetate and
-L-glucose pentaacetate, respectively.
The administration of unesterified
D-glucose (5.5 mM) at the end of
the experiments always resulted in a rapid and significant decrease in
glucagon output, demonstrating the metabolic and functional integrity
of the glucagon-producing cells. As judged by paired comparison of the
mean secretory rates recorded just before introduction of the
unesterified hexose (min 74-78)
and at the end of the perfusion period (min
96-100), the relative extent of the inhibitory
action of D-glucose on glucagon
release averaged 70.0 ± 2.6, 58.2 ± 4.1, and 59.0 ± 6.7% (P < 0.005 or less)
after prior exposure to
-D-glucose pentaacetate,
-L-glucose pentaacetate, and
unesterified D-glucose, respectively. It was thus somewhat more pronounced
(P < 0.05) in the first case than in
the latter two.
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DISCUSSION |
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The present experiments were aimed at comparing the effects of
-D-glucose pentaacetate,
-L-glucose pentaacetate, and
unesterified D-glucose on
insulin, somatostatin, and glucagon release by the isolated perfused
rat pancreas. They were conducted in the presence of
L-leucine (10.0 mM) to increase
the magnitude of the insulin secretory response to the two esters of
glucose (18). The esters were tested at a 1.7 mM concentration, which
is close to their limit of solubility. No sizable hydrolysis of the
esters took place in the perfusate.
The findings illustrated in Figs. 3 and 4 confirm that
-D-glucose pentaacetate and,
to a much lesser extent,
-D-glucose pentaacetate
stimulate insulin release under experimental conditions in which
unesterified D-glucose, tested
at the same molar concentration, fails to do so. As already mentioned
in the introduction, the insulinotropic action of the hexose esters
cannot be attributed to the catabolism of their acetate moieties.
Likewise, in the case of
-L-glucose pentaacetate, the
stimulation of insulin release cannot be due to the catabolism of the
hexose moiety of the ester, since
L-glucose is not phosphorylated
by hexokinase isoenzymes (unpublished observation). The secretory
response to this ester thus appears unrelated to its nutritional value
and, instead, could be due to a direct effect of the ester itself on
some as-of-yet unidentified receptor system.
In addition to its vastly lower magnitude, the secretory response of
the B cells to -L-glucose
pentaacetate differed from that evoked by
-D-glucose pentaacetate by
the virtual absence of an early secretory peak and the absence of a
residual insulinotropic action when the administration of the ester was
interrupted.
These two differences may well be attributable to the capacity of
-D-glucose pentaacetate, as
distinct from
-L-glucose
pentaacetate, to generate
D-glucose by intracellular
hydrolysis of the ester with further phosphorylation and metabolism of
this hexose in the islet cells (20). Such a metabolic component of the
secretory response could indeed be required to allow for the occurrence of an early secretory peak. It may also account for the existence of a
residual stimulation of insulin release after removal of the ester from
the perfusate. Indeed, the large amounts of the ester that accumulate
in islet cells (20) may be sufficient to maintain for some time a
sizable glycolytic flux.
Many of the considerations so far presented may also apply to the
secretion of somatostatin. Such is the case, for instance, for the
difference between -D-glucose
pentaacetate and
-L-glucose pentaacetate in terms of the magnitude of the secretory response to
these esters and their residual effect on hormonal output when removed
from the perfusate. Likewise, both the insulin and somatostatin release
evoked by unesterified D-glucose
at the end of the experiments was somewhat higher after prior exposure
to a glucose ester than after prior administration of unesterified
D-glucose.
The secretory behavior of the D cells differed, however, from that of B
cells in two major respects. First, in response to -D-glucose pentaacetate
administration, no early peak-shaped release of somatostatin could be
detected, at variance with the secretory pattern found, within the same
experiments for insulin release. Second, as computed over periods of 22 min, the paired ratio between insulin output in the presence of the
glucose esters (min 29-50) and
unesterified D-glucose
(min 79-100) was about one
order of magnitude higher in the case of somatostatin than insulin
release. Thus such ratios averaged, in the experiments conducted in the
presence of
-D-glucose
pentaacetate and
-L-glucose pentaacetate, respectively, 98.8 ± 14.2 and 8.4 ± 2.0% in the case of insulin release, as distinct
(P < 0.001) from 548.5 ± 110.6 and 161.6 ± 42.3% in the case of somatostatin
secretion. These findings suggest that the relative contribution of the
two postulated components of the secretory effects of glucose esters, i.e., the metabolic component linked to the catabolism of their hexose
moieties and the direct effect of the esters themselves, is not
identical in B and D cells. This view is further supported by the fact
that, relative to the mean value found with
-D-glucose pentaacetate, the
steady-state secretory rate found between the 46th and 50th min of
exposure to
-L-glucose
pentaacetate was lower, whether expressed in absolute terms or relative
to basal output, in the case of insulin than somatostatin release, with overall mean values of 8.0 ± 1.6 and 41.2 ± 12.4%
(P < 0.02).
The most dramatic evidence for the postulated dual mode of action of
the glucose esters in the endocrine pancreas was provided by the
measurements of glucagon release. Thus the two esters first stimulated
glucagon secretion in a comparable manner, whether in terms of the
magnitude or time course of this early secretory response, suggesting
that such a glucagonotropic action is unrelated to the nutritional
value of the esters. However, the two series of experiments differed
from one another by the fact that
-D-glucose pentaacetate, but
not
-L-glucose pentaacetate,
inhibited glucagon release during the late period of exposure to the
esters, this effect being reversed after removal of
-D-glucose pentaacetate from
the perfusate. Likewise,
-D-glucose pentaacetate, but
not
-L-glucose pentaacetate,
apparently primed the glucagon-producing cells to the inhibitory action
of unesterified D-glucose
administered at the end of the experiments. The latter two phenomena
are likely to result from the metabolism of the hexose moiety of
-D-glucose pentaacetate,
since they indeed duplicate the effect of unesterified D-glucose on the secretory
behavior of A cells. The inhibitory action of the hexose on glucagon
release is indeed well known. Likewise, several reports have already
documented that prior exposure of the pancreas to
D-glucose decreases the
secretory response of
2-cells
to the subsequent administration of arginine (3, 4). To our knowledge,
however, the results obtained in the experiments conducted with
-D-glucose pentaacetate
provide the first evidence for A cell priming in terms of the
inhibitory action of D-glucose
on glucagon output.
It should also be stressed that in the present experiments, unesterified D-glucose, when tested at the low concentration of 1.7 mM, obviously inhibited glucagon release despite failing to cause any sizable increase in insulin release. This finding is compatible with the view that the hexose can inhibit glucagon secretion independently of any stimulation of insulin secretion (9).
In conclusion, the present findings convincingly document that glucose
esters, such as -D-glucose
pentaacetate and
-L-glucose pentaacetate, affect insulin release through a dual mode of action and
extend such a knowledge to the secretion of both somatostatin and
glucagon by the endocrine pancreas. In our opinion, advantage could be
taken of the fact that esters of nonmetabolizable hexoses stimulate
insulin release by an as-of-yet unknown mechanism, to develop new
insulinotropic tools for the treatment of non-insulin-dependent diabetes (12, 14).
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ACKNOWLEDGEMENTS |
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We are grateful to J. Marchand for technical assistance and to C. Demesmaeker for administrative help.
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FOOTNOTES |
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This study was supported by a Concerted Research Action (94-99/183) of the French Community of Belgium and a grant (3.4513.94) from the Belgian Foundation for Scientific Medical Research.
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: W. J. Malaisse, Laboratory of Experimental Medicine, Brussels Free Univ. (CP 618), 808 Route de Lennik, B-1070 Brussels, Belgium.
Received 10 February 1998; accepted in final form 24 June 1998.
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