Department of Pharmacology, University of Lund, S-223 62 Lund, Sweden
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ABSTRACT |
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An important signal involved in
glucose-stimulated insulin secretion is transduced through the action
of a lysosomal acid, glucan 1,4--glucosidase. We investigated the
Ca2+ dependency of this enzyme
activity in relation to insulin release. In isolated islets, increased
levels of extracellular Ca2+
induced a large increase in acid glucan 1,4-
-glucosidase activity accompanied by a similar increase in insulin release at both
substimulatory and stimulatory concentrations of glucose. At low
glucose the Ca2+ "inflow"
blocker nifedipine unexpectedly stimulated enzyme activity without
affecting insulin release. However, nifedipine suppressed 45Ca2+
outflow from perifused islets at low glucose and at
Ca2+ deficiency when intracellular
Ca2+ was mobilized by carbachol.
This nifedepine-induced retention of
Ca2+ was reflected in increased
acid glucan 1,4-
-glucosidase activity. Adding different
physiological Ca2+ concentrations
or nifedipine to islet homogenates did not increase enzyme activity.
Neither selective glucan 1,4-
-glucosidase inhibition nor the ensuing
suppression of glucose-induced insulin release was overcome by a
maximal Ca2+ concentration. Hence,
Ca2+-induced changes in acid
glucan 1,4-
-glucosidase activity were intimately coupled to similar
changes in Ca2+-glucose-induced
insulin release. Ca2+ did not
affect the enzyme itself but presumably activated either glucan
1,4-
-glucosidase-containing organelles or closely interconnected messengers.
pancreatic islets; lysosomal enzymes; nifedipine; emiglitate; carbachol; calcium ion
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INTRODUCTION |
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IT IS A WELL-KNOWN FACT (8, 25, 34, 35) that
Ca2+ plays an essential role in
the stimulus-secretion coupling for insulin release. The cytosolic
accumulation and intracellular distribution of
Ca2+ are important for a growing
number of different events in the secretory process, which is affected
not only by the major secretagogue glucose but also by a variety of
cholinergic, adrenergic, and peptidergic influences (2, 3, 8-10,
12, 22, 25, 33-35). Moreover, glucose-induced insulin release
itself is a complex cascade of events, the details of which are far
from elucidated (2, 25, 35). We have previously proposed (14-20,
28-32) that one of these glucose-induced multiple signals is
transduced via the vacuolar system, involving the activation of a
lysosome-acid glucan 1,4--glucosidase system. The acid glucan
1,4-
-glucosidase (EC 3.2.1.3) and the acid
-glucosidase (EC
3.2.1.20) are members of the
-glucosidehydrolase family. The acid
glucan 1,4-
-glucosidase is known to preferentially attack
-1,4-linked polymers such as glycogen (24) and thereby to have the
ability to produce high local concentrations of
nonphosphorylated glucose within the vacuolar system. This glucose
production, in turn, could act as a transducer (e.g., metabolic,
osmotic, or cybernetic) in the multifactorial process of insulin
release. Glycogen is a normal constituent of islet tissue (11, 21), and
it is known to display a surprisingly constant concentration at a wide
range of blood glucose levels (21). Hence an important part of islet
glycogen is probably not integrated in the metabolic pool of glucose
phosphorylation processes in the cytoplasm but rather is restricted to
a compartmentalized vacuolar pool of signal glycogen available to the
acid glucan 1,4-
-glucosidase. It is worth noting that the
phosphorolytic breakdown of glycogen in vitro from mouse islets is
reportedly very slow (21).
In a recent report (28) we showed that the defective glucose-induced
insulin release from isolated mouse islets in a
Ca2+-deficient medium was
accompanied by markedly reduced activities of islet lysosomal
-glucosidehydrolases. In contrast, the activity of another
lysosomal glycosidase,
N-acetyl-
-D-glucosaminidase, was completely unaffected by Ca2+
deficiency. Likewise, islet activities of the lysosomal enzyme acid
phosphatase and the neutral
-glucosidase (endoplasmic reticulum) were not influenced in a
Ca2+-deficient medium. A similar
pattern of a greatly suppressed glucose-induced insulin release in
parallel with a reduced acid
-glucosidehydrolase activity was
accomplished by different selective
-glucosidehydrolase inhibitors
such as miglitol, emiglitate, and acarbose (19, 20 28-32).
Hence, because the activity of the lysosomal acid
-glucosidehydrolases (but not the neutral
-glucosidase) seemed to
be one of several important intracellular key factors in
glucose-induced insulin release, we found it mandatory to study the
Ca2+ dependency of these enzyme
activities in more detail. In the present investigation we tested
1) high concentrations of
extracellular Ca2+,
2) the
Ca2+ channel blocker nifedipine
and the intracellular Ca2+
mobilizer carbachol, as well as 3)
the selective
-glucosidehydrolase inhibitor emiglitate (26) to
further elucidate the role of Ca2+
in regulating islet acid
-glucosidehydrolase activities and insulin
release.
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MATERIALS AND METHODS |
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Animals
Adult female mice of the NMRI strain (B & K Universal, Sollentuna, Sweden), 3-4 mo old and weighing 25-30 g, fed ad libitum, and with free access to water, were used throughout the study. The experiments were approved by the Ethical Committee for Animal Research at the University of Lund.Drugs and Chemicals
Collagenase (CLS 4) was obtained from Worthington Biochemicals (Freehold, NJ). Nifedipine, ethylene glycol-bis(Experimental Procedure
Isolation of pancreatic islets from freely fed mice was accomplished by retrograde injection of a collagenase solution via the bile-pancreatic duct (5). The animals were killed from 8 to 9 AM by elongation of the neck and were immediately injected with collagenase.Batch incubation of isolated islets. The freshly isolated islets were preincubated for 30 min at 37°C in Krebs-Ringer bicarbonate (KRB) buffer, pH 7.4, supplemented with 10 mmol/l N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES), 0.1% bovine serum albumin, and 1 mmol/l glucose. Each incubation vial contained 30 islets in 1.5 ml buffer solution and was gassed with 95% O2-5% CO2 to obtain constant pH and oxygenation. After preincubation, the buffer was changed to a medium containing 1 or 16.7 mmol/l glucose ± test substances, and the islets were incubated for 120 min. Emiglitate, when used, was included also during the preincubation period (20). All incubations were performed at 37°C in an incubation box (30 cycles/min). It should be noted that, in the experiments with high concentrations of Ca2+, phosphate and sulfate in the KRB-HEPES buffer were replaced with equimolar amounts of chloride (9). The change in osmotic pressure with high Ca2+ was compensated for by reduction of NaCl, as described by Hellman (9). Immediately after incubation, an aliquot of the medium was removed for assay of insulin. Insulin was determined radioimmunologically (7).
Lysosomal enzyme activities.
If not otherwise stated, the islets were then thoroughly washed in
glucose-free KRB buffer and collected and stored in 200 µl
acetate-EDTA buffer (1.1 mmol/l EDTA and 5 mmol/l acetate, pH 5.0) at
20°C (14). Ancillary experiments showed that the collected
islets could be kept frozen for several months without loss of enzyme
activity. After sonication, islet homogenates were analyzed for
lysosomal enzyme activities. In experiments in which we studied the
direct influence of different Ca2+
concentrations added to islet homogenates on the lysosomal enzyme activities, the islets were washed in a glucose- and
Ca2+-free KRB buffer and collected
and stored in 5 mmol/l acetate in the absence of EDTA. The procedures
for determination of acid phosphatase (pH 4.5), acid
-glucosidase
(pH 4.0 and 5.0),
N-acetyl-
-D-glucosaminidase (pH 5.0), and neutral
-glucosidase (pH 6.5) with
methylumbelliferyl-coupled substrates have previously been described
(16). Islet glucan 1,4-
-glucosidase activity with glycogen as
substrate was determined at pH 4.0, as described in detail elsewhere
(14, 19). The acid
-glucosidase activity was assayed at both pH 4.0 and pH 5.0, because previous studies (23) have shown that inhibition of
-glucosidase by the lysosomotropic drug suramin was dependent on the
prevailing pH value. Furthermore, it should be recalled that lysosomal
enzyme activities are subjected to circadian and seasonal variations
(see Ref. 6). Therefore, all experiments were always performed with
both control groups and experimental groups at each occasion.
Protein was analyzed according to the method of Lowry et al.
(13).
Islet perifusion experiments. In the perifusion experiments, islets (150-200) were first incubated for 90 min in 800 µl of KRB medium containing 20 mmol/l glucose and 50 µl 45CaCl2 (50-100 µCi), which was added from a stock solution with a specific activity of 10-40 mCi/mg Ca2+. The islets were then washed three times with nonradioactive medium, divided into two or three groups with 75-100 islets per group, and transferred to perifusion columns. The islets were thereby sandwiched between two layers of gel (Bio-gel P-4, 200-400 mesh; Bio-Rad Laboratory, Richmond, CA) and perifused at a rate of 0.1 ml/min with the KRB buffer supplemented with 1 mmol/l glucose. Test substances were introduced according to the protocols. A Ca2+-deficient medium was obtained by omitting calcium chloride and adding 0.5 mmol/l EGTA. The radioactivity lost by the islets was measured in effluent fractions collected every 2 min (50 µl of the sample were added to 5 ml of scintillation fluid) and counted in a scintillation counter (Packard Instrument, Downers Grove, IL). The fractional efflux rate was calculated for each period (radioactivity lost by islets during the time interval/radioactivity present in the islets during the same time interval), and the mean value calculated for minutes 40 and 42 was then normalized to 100%. Insulin was determined with a radioimmunoassay (7).
Statistics
Probability levels of random differences were determined by Student's unpaired t-test or analysis of variance followed by Tukey-Kramer's multiple comparisons test where applicable. ![]() |
RESULTS |
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Effect of a Maximal Concentration of Extracellular Ca2+ on Basal Insulin Release and Islet Lysosomal Enzyme Activities
Taking advantage of a previous dose-response study by Hellman (9) showing that increasing extracellular Ca2+ concentrations up to 30 mmol/l in the presence of a substimulatory glucose level could increase insulin release from isolated ob/ob islets, we performed a series of experiments at 1 mmol/l glucose with either a normal Ca2+ (2.5 mmol/l) or a high maximal (9) concentration of Ca2+ (30 mmol/l) in the extracellular medium. Figure 1 shows that increasing the Ca2+ concentration from 2.5 to 30 mmol/l induced an almost threefold increase in basal insulin release. This enhanced insulin secretion was accompanied by a marked increase in islet lysosomal
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Effects of Direct Addition of Different Concentrations of Ca2+ on Lysosomal Enzyme Activities in Islet Homogenates
Because a high concentration of extracellular Ca2+ greatly increased the acid
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Influence of the Ca2+ Channel Blocker Nifedipine on Islet Lysosomal Enzyme Activities and Insulin Release at Low and High Glucose Concentrations
To further investigate, in intact islets, the effect of Ca2+ perturbations on insulin release in relation to the activities of the acid
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Effects of Direct Addition of Nifedipine on Lysosomal Enzyme Activities in Islet Homogenates
To elucidate whether nifedipine could directly activate the islet
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Effect of Nifedipine on 45Ca2+ Efflux from Isolated Islets Either at Low (1 mmol/l) Glucose and Normal Ca2+ or in a Ca2+-Deficient Medium in Which the Islets Were Stimulated by the Intracellular Ca2+ Mobilizer Carbachol at Low Glucose
Because high extracellular Ca2+ (Fig. 1) as well as nifedipine (Fig. 4) could increase the acid
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Effect of Nifedipine on Islet Lysosomal Enzyme Activities and Insulin Release in a Ca2+-Deficient Medium in the Presence and Absence of the Intracellular Ca2+ Mobilizer Carbachol
The next experiment was performed to test whether the carbachol-mobilized Ca2+, which was retained within the
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Effect of a Maximal Concentration of Extracellular
Ca2+ on
Glucose-Stimulated Insulin Release and Islet Lysosomal Enzyme
Activities in the Absence and Presence of the Selective
-Glucosidehydrolase Inhibitor Emiglitate
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DISCUSSION |
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The present results lend further support to our previous hypothesis
(14-20, 28-32) that one of the multiple signals involved in
glucose-induced insulin release is transduced through the activation of
a glycogen-hydrolyzing acid, glucan 1,4--glucosidase.
Effects of Ca2+ Deficiency and High Extracellular Ca2+
In a recent study we reported (28) that the activities of the acidEffects of Blockade of Ca2+ Influx by Nifedipine and of Intracellular Ca2+ Mobilization by Carbachol
Because high extracellular Ca2+ enhanced the acidThe putative Ca2+ redistribution
leading to activation of the acid -glucosidehydrolases seemed in no
way obligatory to the inflow of extracellular
Ca2+ through the voltage-dependent
Ca2+ channels, because enzyme
activity could be induced by nifedipine in a
Ca2+-deficient medium. From these
experiments it is also obvious that the nifedipine-stimulated
Ca2+ redistribution and the
subsequent increase in acid glucan 1,4-
-glucosidase activity are not
sufficient by themselves to induce an insulin secretory response,
because nifedipine at the same time blocks the voltage-dependent
Ca2+ channels. Furthermore, it
seems very unlikely that Ca2+
itself is directly modulating the enzyme(s), because physiological [Ca2+]i
(10, 25, 27, 33) in both the absence and presence of calmodulin did not
display any notable effect on the enzyme activities after addition to
islet homogenates. It should be noted, however, that very high
concentrations of Ca2+ (2 mmol/l-30 mmol/l) did activate considerably the acid glucan 1,4-
-glucosidase but inhibited the acid
-glucosidases (Fig. 2).
Such high Ca2+ concentrations are
not likely to occur intracellularly, although theoretically they cannot
be completely ruled out in certain
Ca2+-rich subcellular compartments
and organelles. Furthermore, this highly differential action of 2 and
10 mmol/l Ca2+ on the acid glucan
1,4-
-glucosidase, compared with the acid
-glucosidases
in islet homogenates, was indeed not reflected in the various
experiments with isolated intact islets, where these activities were
always increased by the supraphysiological extracellular
Ca2+ concentrations used in our
studies (see Figs. 1 and 8).
With regard to glucose-stimulated insulin release, it is conceivable
that the initial glucose-induced decrease in
45Ca2+
efflux (3), which was recently shown to be the result of the ability of
glucose to induce sequestration of cytoplasmic
Ca2+ in a slowly exchangeable
"organelle pool" (10), may be a key event in this context.
Interestingly, the glucose-induced redistribution and sequestration of
intracellular Ca2+ are manifested
earlier and at lower glucose concentrations than those required to open
the voltage-dependent Ca2+
channels (10). It is not inconceivable that one of these sequestration targets is the acid glucan 1,4--glucosidase-containing organelles. Such an assumption is in accordance with previous data showing, in a
Ca2+-deficient medium, that an
increase in glucose concentration from 1 to 4 mmol/l also increased the
acid
-glucosidehydrolase activities (28). Hence, in addition to
other factors, glucose-stimulated insulin release is apparently
dependent on both a redistribution and a sequestration of intracellular
Ca2+, which in turn activate the
lysosomal-acid glucan 1,4-
-glucosidase system as well as the inflow
of extracellular Ca2+ through
voltage-dependent Ca2+ channels at
depolarizing glucose concentrations. This redistribution/sequestration hypothesis also conforms with recent observations (29) showing that the
acid
-glucosidehydrolase activities were profoundly suppressed in
islets incubated in a
Ca2+-deficient medium in the
presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine
(IBMX), which is known to induce perturbations of intracellular
organelle-bound Ca2+ in the
-cell (2).
Effects of the Selective -Glucosidehydrolase
Inhibitor Emiglitate
In summary, in intact islets, high supraphysiological concentrations of
extracellular Ca2+ brought about a
marked enhancement of the islet acid -glucosidehydrolase activities,
accompanied by a large insulin release. The
Ca2+ channel blocker nifedipine
unexpectedly brought about an increase in acid
-glucosidehydrolase
activity at low glucose. This increase was explained by showing that
nifedipine suppressed
45Ca2+
outflow from perifused islets at substimulatory glucose and normal Ca2+, as well as after
intracellular mobilization of
45Ca2+
by carbachol in a Ca2+-deficient
medium. The inhibition of
45Ca2+
efflux was probably accomplished through increased intracellular sequestration and impaired outflow of
Ca2+ across the plasma membrane.
The Ca2+-induced effects were
shown not to be exerted by a direct action of either nifedipine or
Ca2+ on the acid
-glucosidehydrolases. Instead we suggest that this signal function
of Ca2+ is exerted on a step
closely proximal to enzyme activation, e.g., on certain membrane
constituents of acidic organelles and/or key factor(s)
modulating the acid
-glucosidehydrolases in their in vivo catalytic
function. This was further emphasized by the finding that selective
inhibition of the acid
-glucosidehydrolases by emiglitate almost
abolished glucose-induced insulin release, an effect which could not be
overcome by increased Ca2+. Taken
together with data on islet acid
-glucosidehydrolase activities
obtained from previous experiments in
Ca2+-deficient media (28), a
redistribution of Ca2+ induced by
glucose (or by pharmacological agents such as nifedipine) that is
directed to acid
-glucosidehydrolase-containing organelles appears
an attractive mechanism in this context. The intimate details of
Ca2+ redistribution,
sequestration, and induction of acid glucan 1,4-
-glucosidase activity in nutrient-induced insulin release will await further investigations.
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ACKNOWLEDGEMENTS |
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The skillful assistance of Elsy Ling and Britt-Marie Nilsson and the secretarial help of Eva Björkbom and Björn Otterlin are gratefully acknowledged.
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FOOTNOTES |
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This study was supported by the Swedish Medical Research Council (14X-4286), the Crafoord Foundation, the Swedish Diabetes Association, the Albert Påhlsson Foundation, and the Åke Wiberg Foundation.
Address for reprint requests: A. Salehi, Dept. of Pharmacology, Sölvegatan 10, S-223 62 Lund, Sweden.
Received 12 June 1997; accepted in final form 24 November 1997.
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