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J Biol Chem, Vol. 273, Issue 51, 33905-33908, December 18, 1998
Cells but Not in 
Cells and Are
Also Observed in Human Islets*
,
From the Glucose metabolism by pancreatic Glucose homeostasis is largely regulated in the endocrine pancreas
through opposite effects of glucose on insulin and glucagon secretion.
Pancreatic Although early studies reported that glucose increases ATP levels in
rodent islets (16, 17), a rise in the ATP/ADP ratio was not a
consistent finding (reviewed in Ref. 18). Recently, we demonstrated
that glucose causes a large, concentration-dependent increase in the ATP/ADP ratio in mouse islets and that this effect might be involved in the regulation of insulin secretion through both
pathways (19, 20). However, the changes measured in whole islets might
not exactly reflect those occurring in The present study compares the effect of glucose on adenine nucleotides
in purified rat Preparation and Purification of Rat Islet Cells--
Rat islet
In a first series of experiments, the islets were cultured overnight in
Ham's F-10 medium supplemented with 2 mM glutamine, 10 mM glucose, 1% bovine albumin, and 5% fetal calf serum.
They were then used to obtain three fractions of dispersed islet cells (20%
In a second series of experiments, the dispersion of islet cells and
their purification immediately followed the islet isolation. Purified
Measurements of Adenine Nucleotides in Rat Islet Cells--
The
medium used was a bicarbonate-buffered solution that contained 120 mM NaCl, 4.8 mM KCl, 2.5 mM
CaCl2, 1.2 mM MgCl2, 1 mM Na2HPO4, and 24 mM
NaHCO3. It was gassed with O2:CO2
(94:6) to maintain pH 7.4 and was supplemented with 1% bovine serum albumin.
Cell preparations were first washed twice with this medium before
batches of 15,000-50,000 cells were incubated for 1 h in 375 µl
of medium supplemented with different glucose concentrations. The
incubation was stopped by the addition of 125 µl of trichloroacetic acid to a final concentration of 5%. The samples were then processed, and ATP and ADP were measured by a luminometric method exactly as
described previously (20).
Measurements of Glucose Oxidation by Rat Islet
Cells--
Batches of ~100,000 cells from the different cellular
fractions were incubated for 2 h in 100 µl of Earle's-Hepes
buffer (24) containing the indicated concentration of glucose and
supplemented with 25 µCi/ml [U-14C]glucose. The
incubation was stopped by the addition of 20 µl of 1 N
HCl and 14CO2 was trapped with hydroxyhyamine.
Other details of the method have been published (24).
Experiments with Human Islets--
Human pancreata were obtained
from organ donors (19-61 years of age) within the framework of The nucleotide content of the different cell preparations was
measured after 1 h of incubation in the presence of various glucose concentrations (Fig. 1). In
dispersed, unsorted, islet cells, ATP levels were 75% higher at 10 than 1 mM glucose (Fig. 1A), whereas ADP levels
were 45% lower (Fig. 1B). This resulted in an increase in
the ATP/ADP ratio from 3.8 at 1 mM glucose to 12.3 at 10 mM glucose (Fig. 1C). ATP and ADP levels were
slightly lower in purified The rate of glucose oxidation was similar in The islet non- Unit of Endocrinology and Metabolism,
ABSTRACT
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Abstract
Introduction
Procedures
Results
Discussion
References
and 
cells is essential for stimulation of insulin secretion and
inhibition of glucagon secretion. Studies using rodent islets have
suggested that the ATP/ADP ratio serves as second messenger in cells. This study compared the effects of glucose on glucose oxidation
([U-14C]glucose) and adenine nucleotides
(luminometric method) in purified rat and cells. The rate of
glucose oxidation at 1 mM glucose was higher in than
cells (4.5-fold, i.e. ~2-fold after normalization for
cell size). It was more strongly stimulated by 10 mM
glucose in cells (9-fold) than in cells (5-fold). At 1 mM glucose, ATP levels were similar in both cell types,
which corresponds to an approximately 2-fold higher concentration in
cells (~6.5 mM) than in cells (~3
mM). In cells, glucose dose-dependently increased ATP and decreased ADP levels, causing a rise in the ATP/ADP
ratio from 2.4 to 11.6 at 1 and 10 mM, respectively. In cells, glucose did not affect ATP and ADP levels, and the ATP/ADP ratio
remained stable around 7.5. In human islets, the ATP/ADP ratio
progressively increased between 1 and 10 mM glucose. In duct cells, which often contaminate human islet preparations, an
increase in the ATP/ADP ratio sometimes occurred between 1 and 3 mM glucose. In conclusion, the present observations
establish that the regulation of glucagon secretion by glucose does not involve changes in cell adenine nucleotides and further support the
role of the ATP/ADP ratio in the control of insulin secretion.
INTRODUCTION
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Abstract
Introduction
Procedures
Results
Discussion
References
cells are fuel sensors that adjust the rate of insulin
secretion to the rate at which they metabolize glucose (reviewed in
Refs. 1-3). Two major transduction pathways are involved. The first
one uses ATP-sensitive K+ channels (K+-ATP
channels) of the plasma membrane to transduce biochemical into
biophysical signals. Thus, glucose metabolism causes closure of these
K+-ATP channels, which leads to membrane depolarization,
opening of voltage-dependent Ca2+ channels, and
acceleration of Ca2+ influx. The resulting rise in
cytoplasmic Ca2+ concentration
([Ca2+]i) then triggers exocytosis of insulin
granules (reviewed in Refs. 4-6). The second pathway, known as the
K+-ATP channel-independent pathway, increases the
effectiveness of Ca2+ on exocytosis by as yet incompletely
elucidated mechanisms (7-9). Much less information is available on how
glucose inhibits glucagon secretion from cells (10). Measurements
of glucose metabolism in cell-rich islets (11) and purified cells (12) and studies using metabolic inhibitors in whole islets or
pancreas (13-15) suggest that the inhibition of glucagon secretion is
mediated by glucose metabolism in the cells.
cells. It is also not known
whether glucose affects adenine nucleotides in cells. Measurements
in islets isolated from animals made diabetic by destruction of most of
their cells with streptozotocin are indeed contradictory (21,
22).
and cells (23). It also examines whether the
changes observed in rodent cells are seen in isolated human islets.
EXPERIMENTAL PROCEDURES
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Abstract
Introduction
Procedures
Results
Discussion
References
and cells were purified from adult male Wistar rats by
autofluorescence-activated cell sorting using previously described
methods (23).
cells and 65% cells), purified cells (>90%), and
non- cells (~70% cells, 5-10% cells, and 10-15% other
cells). These purities were checked by immunocytochemistry (23). The
three fractions were then incubated as described below for measurements of glucose oxidation and adenine nucleotide content.
cells were then cultured overnight in Ham's F-10 medium supplemented with 2 mM glutamine, 10 mM
glucose, 2 mM CaCl2, and 1% bovine serum
albumin. Non- cells were first separated from cells and then
purified into cells (>85% cells, <5% cells), which were
then cultured overnight in Ham's F-10 medium supplemented with 2 mM glutamine, 6 mM glucose, and 1% bovine
serum albumin. Purified and cells were then incubated as
described below for measurement of glucose oxidation and adenine
nucleotide content.
Cell Transplant, a European Concerted Action on islet transplantation.
After isolation, the islet preparations were cultured for 2-3 days as
described elsewhere (25); their cellular composition was similar to
that in our previous studies (25). They were then incubated for 1 h in bicarbonate-buffered medium containing the indicated glucose
concentration before being processed for nucleotide measurements.
RESULTS
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Abstract
Introduction
Procedures
Results
Discussion
References
cells, but their relative changes were
slightly larger, resulting in an increase in the ATP/ADP ratio from 3.2 to 14.8 between 1 and 10 mM glucose. In islet non-
cells, the ATP content was similar to that in cells at 1 mM glucose but did not change when the glucose
concentration was raised (Fig. 1A). ADP levels were lower
and decreased by 40% between 1 and 10 mM glucose. Thus, as
compared with cells, the ATP/ADP ratio in islet non- cells was
higher at 1 mM glucose but increased much less at 10 mM glucose. In no fraction were ATP or ADP levels different
between 10 and 20 mM glucose.
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Fig. 1.
Effects of various concentrations of glucose
on nucleotide levels and glucose oxidation in purified rat cells,
non- cells, and islet cells. Nucleotides were measured in cells
incubated for 1 h in a medium containing the indicated glucose
concentration. Glucose oxidation was measured as
14CO2 production from
[U-14C]glucose by cells incubated for 2 h. Values
are means ± S.E. for six batches of cells from three separate
experiments (nucleotides) or three to six individual experiments
(oxidation).
cells and unsorted
islet cells; it increased 8-fold ( cells) and 6-fold (islet cells)
when the concentration of glucose was raised from 1 to 10 mM (Fig. 1D). The rate of glucose oxidation was
lower in non- cells than in cells, both at low and high glucose;
it increased 4-fold between 1 and 10 mM glucose.
cell fraction is enriched in cells but may
contain up to 15% cells and up to 20% other cell types (12). The
observed changes in glucose oxidation and nucleotide levels might thus
take place, at least in part, in cells other than the cells. We
therefore purified the islet non- cells into a fraction containing
over 80% cells. Fig. 2A
shows that the ATP content of and cells was similar after
incubation in 1 mM glucose and that glucose increased this
content more than 2-fold in cells without affecting it in cells. In cells, ADP levels decreased when the glucose
concentration was raised (Fig. 2B). The ADP content of cells was 3-fold lower and did not change with the glucose
concentration. As a result, the ATP/ADP ratio in cells increased
more than 4-fold between 1 and 10 mM glucose, whereas the
elevated ratio in cells at low glucose was not modified by a higher
glucose concentration (Fig. 2C). All changes occurring in
cells between 1 and 5 mM glucose were significant
(p < 0.05 or less), but there was no difference
between measurements at 10 and 20 mM glucose.
View larger version (18K):
[in a new window]
Fig. 2.
Effects of various concentrations of glucose
on nucleotide levels and glucose oxidation in purified rat and cells. Nucleotides were measured in cells incubated for 1 h
in a medium containing the indicated glucose concentration. Glucose
oxidation was measured as 14CO2 production from
[U-14C]glucose by cells incubated for 2 h. Values
are means ± S.E. for 15 batches of cells from five separate
experiments (nucleotides) or for five individual experiments
(oxidation).
The rate of glucose oxidation was higher in than cells (Fig.
2D). The difference was larger at 10 mM glucose
(8-fold) than at 1 mM glucose (4.5-fold) because the
oxidation rate was more strongly increased by glucose in cells
(9-fold) than in cells (5-fold).
In human islets, glucose increased the ATP/ADP ratio dose-dependently (Fig. 3). Because these preparations can contain up to 40% non-endocrine cells (mainly duct cells), we also measured the effects of glucose on the ATP/ADP ratio in duct cells. This ratio increased between 1 and 3 mM glucose and then plateaued; for unknown reasons the increase was observed in only four of seven preparations. The consequence is that the observed rise in ATP/ADP ratio in human islet preparations may partly reflect changes occurring in duct cells, at least between 1 and 3 mM glucose. The dotted line in Fig. 3 shows calculated values for islet cells after correction for events in 20% contaminating duct cells.
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DISCUSSION |
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Abstract
Introduction
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Results
Discussion
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The present study shows that glucose exerts strikingly different
effects on adenine nucleotides in insulin- and glucagon-secreting cells. It does not change the ATP/ADP ratio in cells and increases it in cells from the rat. The study also establishes that glucose increases the ATP/ADP ratio in human islets.
Two previous studies have used islets obtained from rat (21) or guinea
pigs (22) made cell-deficient and diabetic with streptozotocin to
estimate ATP levels in cells. In one study no difference in islet
ATP content was observed between 0 and 10 mM glucose (21),
whereas a 25% increase occurred between 1.7-3.3 and 16.7 mM glucose in the other study (22). ADP contents were not
reported. The discrepancy between these studies and the increase in ATP
levels that insulin caused in these cell-rich islets of diabetic
animals (22, 26) left unanswered the question of whether glucose
influences adenine nucleotides in normal cells. In preparations of
islet non- cells, the composition of which is comparable with that
of cell-enriched islets, glucose slightly increased the ATP/ADP
ratio, mainly through a decrease in ADP. However, these changes can be
ascribed to contaminating non- cells, in particular 10-15% of
residual cells with their larger volume (12). Thus, the experiments
using purified cells unambiguously showed that the ATP/ADP ratio is
not influenced by glucose (1-10 mM) in glucagon-secreting
cells from normal rats.
The observation that the ATP/ADP ratio does not change in
glucose-challenged cells implies that the measurements in whole islets underestimate the actual changes occurring in cells unless the ratio decreases in 
cells. This is very unlikely owing to the
similarities of stimulus-secretion coupling in and cells (15).
In practice, because 65% of cells make up at least 80% of the
islet volume in the rat (27) and 80% of cells make up close to
90% of the islet volume in the mouse (28), the adenine nucleotide
measurements in intact islets should satisfactorily reflect the changes
occurring in cells. However, in human islet preparations, the
results may be variably influenced by the degree of contamination with
duct cells in which the ATP/ADP ratio is influenced by glucose, at
least in the low concentration range (1-3 mM).
Pancreatic and cells have different sizes that must be taken
into account in a comparison of their nucleotide contents. The
intracellular space is about 2.3-fold larger in than in non-
cells from the rat (620 versus 270 pl/103 cells)
(12, 29). From these values it can be calculated that the ATP
concentration increased from ~3 to ~7 mM in cells
and remained around 6.5 mM in cells when the
concentration of glucose was raised from 1 to 10 mM.
Conversely, the concentration of total ADP decreased from ~1.2 to 0.6 mM in cells and was stable around 0.9 mM in
cells. It is important to realize that these values do not exactly
correspond to the nucleotide concentrations in the cytoplasm. ATP and
ADP, in a ratio close to 1.0, are present in insulin-containing
granules (30-32). It is likely that adenine nucleotides are also
present in glucagon-containing granules, but this has not been directly
demonstrated. Another possible confounding factor is the degree of
granulation of the two cell types. If one postulates that the relative
granular pool of adenine nucleotides is similar in both cell types, and cells would seem to have similar cytoplasmic concentrations of
ATP in the presence of high glucose. The peculiar feature of cells
appears to be an inability to maintain these high values when the
concentration of glucose decreases, but the fact that substantial
changes in the ATP/ADP ratio occur between 10 and 5 mM
glucose clearly indicates that they do not express mere suffering of
fuel-deprived cells.
The metabolic organization of and cells has recently been
compared (12, 24). After normalization for the differences in cell
volume, the rate of glycolysis is similar probably because of the
presence of a glucokinase in both cell types (33). However, the ratio
of lactate dehydrogenase/mitochondrial glycerol-3-phosphate dehydrogenase is lower in cells than in cells, cells
express much more pyruvate carboxylase than cells, and glycolysis
is largely aerobic in cells and anaerobic in cells (24). In the
present study basal glucose oxidation (at 1 mM glucose) was lower in non- and purified cells than in cells, but this difference is largely attenuated after correction for the difference in
cell size. Upon stimulation with 10 mM glucose, the
relative increase in oxidation was larger in cells (8-9-fold) than
in non- or cells (4-5-fold). A tight coupling of glycolysis
with pyruvate oxidation and ATP production in mitochondria may explain why the ATP/ADP ratio changes so much with the glucose concentration in
cells. These variations and a high anaplerosis of glucose-derived carbons (24) may be the two major metabolic features distinguishing and cells.
The lack of effect of glucose on the ATP/ADP ratio in cells is a
general metabolic feature shared by many cell types (34-36), whereas
the large variations occurring in cells are exceptional from a
metabolic standpoint. It is therefore tempting to speculate that these
variations have a functional significance. The changes in the ATP/ADP
ratio induced by glucose may regulate insulin secretion via the
K+-ATP channel-dependent and -independent
pathways (20, 37). K+-ATP channels have not been identified
in guinea pig cells (38) but are present in rat cells (39, 40).
However, the data presented here and the characteristics of the cell electrical activity (38, 40) do not support a role for these
channels in the regulation of glucagon secretion by glucose. Mechanisms other than changes in adenine nucleotides should be sought to explain
how glucose inhibits glucagon secretion.
The current model of stimulus-secretion coupling in the pancreatic cell has been built on experiments with rodent islets. Studies with
human islets have shown that it can largely be extrapolated to the
human cell. In particular, the key role of glucose metabolism in
the control of K+-ATP channels, membrane potential, and
cytoplasmic [Ca2+]i has been verified (41, 42).
The present study validates an additional important extrapolation: the
metabolism of glucose in human islets is followed by an increase in the
ATP/ADP ratio, which may thus play a universal role of second messenger in the regulation of insulin secretion.
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ACKNOWLEDGEMENTS |
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We thank the technical staff of Cell
Transplant and the VUB-Diabetes Research Center for preparing the human
and rat cell preparations and F. Knockaert for assistance with the
nucleotide assays.
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FOOTNOTES |
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* This work was supported by Grant P 4/21 from the Interuniversity Poles of Attraction Programme, Belgian State, Prime Minister's Office, and by Grant ARC 95/00-188 from the General Direction of Scientific Research of the French Community of Belgium, Grants 3.4552.98, G 3127.93, and G 0376.97 from the Belgian Foundation for Scientific and Medical Research, Grant BMH4-CT 95-1561 from the European Community-Biomed II, and Grant DIRG 1995-2000 from the Juvenile Diabetes Foundation International.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.
¶ Research fellow from the Fonds voor Wetenschappelijk Onderzoek, Vlaanderen.
To whom correspondence should be addressed: Unité
d'Endocrinologie et Métabolisme, UCL 55.30, Avenue Hippocrate
55, B 1200 Brussels, Belgium. Tel.: 32-2-7645529; Fax:
32-2-7645532.
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Abstract
Introduction
Procedures
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Discussion
References
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