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Department of Pharmacology, University of Lund (A.S., R.H., H.M., I.L.), S-223 62 Lund; and the Department of Endocrinology, Karolinska Institute and Hospital (C.-G.O., S.E.), S-17176 Stockholm, Sweden
Address all correspondence and requests for reprints to: Prof. Ingmar Lundquist, M.D., Ph.D., Department of Pharmacology, University of Lund, Solvegatan 10, S-223 62 Lund, Sweden. E-mail: ingmar.lundquist{at}farm.lu.se
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-glucosidase. We
have analyzed the function of the lysosomal system/lysosomal enzyme
activities in pancreatic islets of young (6–8 weeks), spontaneously
diabetic, GK (Goto-Kakizaki) rats and Wistar control rats in relation
to glucose-induced insulin release. The insulin secretory response to
glucose was markedly impaired in the GK rat, but was restored by the
adenylate cyclase activator forskolin. Islet activities of classical
lysosomal enzymes, e.g.. acid phosphatase,
N-acetyl-ß-D-glucosaminidase,
ß-glucuronidase, and cathepsin D, were reduced by 20–35% in the GK
rat compared with those in Wistar controls. In contrast, the activities
of the lysosomal -glucosidehydrolases, i.e.. acid
glucan-1,4--glucosidase and acid -glucosidase, were increased by
40–50%. Neutral -glucosidase (endoplasmic reticulum) was
unaffected. Comparative analysis of liver tissue showed that lysosomal
enzyme activities were of the same magnitude in GK and Wistar rats.
Notably, in Wistar rats, the activities of acid
glucan-1,4--glucosidase and acid -glucosidase were approximately
15-fold higher in islets than in liver. Other lysosomal enzymes did not
display such a difference. Normalization of glycemia in GK rats by
phlorizin administered for 9 days did not influence either the
lysosomal -glucosidehydrolase activities or other lysosomal enzyme
activities in GK islets. Finally, the pseudotetrasaccharide
acarbose, which accumulates in the lysosomal system,
inhibited acid glucan-1,4--glucosidase activity in parallel with its
inhibitory action on glucose-induced insulin release in intact Wistar
islets, whereas no effect was recorded for either parameter in intact
GK islets. In contrast, acarbose inhibited the enzyme
activity equally in islet homogenates from both GK and Wistar rats,
showing that the catalytic activity of the enzyme itself in disrupted
cells was unaffected. We propose that dysfunction of the islet
lysosomal/vacuolar system is an important defect impairing the
transduction mechanisms for glucose-induced insulin release in the GK
rat. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-glucosidase (3, 4, 5, 6, 7, 8, 9, 10, 11), a member of the
-glucosidehydrolase family of enzymes. This lysosomal
glucose-producing enzyme preferentially cleaves -1,4-linked glucose
polymers and might thus attack certain pools of islet vacuolar glycogen
to produce high local concentrations of free glucose, which, in turn,
could act as a transducer (cybernetic, metabolic, or osmotic) in the
multifactorial process of insulin secretion. Hence, in accordance with
this idea, a close relationship between islet acid
glucan-1,4--glucosidase activity and insulin release was recently
observed in a series of experiments with isolated islets, where three
different and selective -glucosidehydrolase inhibitors,
i.e. emiglitate, miglitol, and acarbose, were
found to suppress glucose-stimulated insulin release in parallel with
their inhibitory effect on islet glucan-1,4--glucosidase activity
(6, 7, 8, 9, 10, 11, 12). Moreover, previous in vivo experiments (3, 4, 13, 14) showed a positive correlation between islet
glucan-1,4--glucosidase activity and glucose-stimulated insulin
secretion both in normal mice and in the insulin-hypersecreting
ob/ob mouse, an animal model of the obese type of
noninsulin-dependent diabetes mellitus (NIDDM), whose islets display a
good insulin response to glucose. The question then arose whether other
types of spontaneous NIDDM in animals, e.g. with a reduced
insulin response to glucose, would disclose any impairment in the link
between lysosomes/lysosomal enzyme activities and glucose-induced
insulin release.
The aim of the present investigation was therefore to study whether a
nonobese animal model of NIDDM, the Goto-Kakizaki (GK) rat, which in
contrast to the ob/ob mouse is known to have a very poor
insulin response to glucose (15, 16, 17, 18), would display any putative
dysfunction in the relation between the islet lysosomal
system/lysosomal acid -glucosidehydrolase activities and insulin
storage and secretion. Additionally, we performed comparative analyses
of lysosomal enzyme activities in liver tissue. The GK rat is known as
a nonobese mildly diabetic rat that was developed by inbreeding Wistar
rats with the highest blood glucose levels during an oral glucose
tolerance test (15, 16), and recent studies have shown that their
diabetic state may be mainly explained by a defect in glucose-induced
insulin secretion, which was markedly impaired in both perfused
pancreas and isolated islets of these rats (17, 18). In the present
study we used one fuel secretagogue, glucose, and the adenylate cyclase
activator forskolin, as the interaction between glucose, on the one
hand, and the cAMP system, on the other, is known to play a pivotal
role in the appropriate release of insulin (2). Moreover, data from our
previous experiments have suggested that glucose-induced insulin
release, but not cAMP-activated insulin release, is dependent on islet
acid glucan-1,4--glucosidase activity and normal function of the
lysosomal/vacuolar system (4, 6, 7, 9, 13, 19). We also studied islet
lysosomal function in GK rats treated for 9 days with phlorizin to test
whether normalization of their blood glucose levels would affect the
lysosomal system. Finally, we investigated in both GK and Wistar rats
the ability of the pseudotetrasaccharide acarbose, a
potent inhibitor of islet acid glucan-1,4--glucosidase (9), to enter
into the lysosomal system and modulate enzyme activity as well as
glucose-induced insulin secretion.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Drugs and chemicals
Collagenase (CLS 4) was obtained from Worthington Biochemical Corp. (Freehold, NJ). Forskolin, phlorizin, and
methylumbelliferyl-coupled substrates were purchased from Sigma Chemical Co. (St. Louis, MO). BSA was obtained from ICN Biomedicals, Inc. (High Wycombe, UK). The pseudotetrasaccharide
acarbose was supplied by Bayer Corp.
(Leverkusen, Germany). All other chemicals were purchased from
Merck & Co., Inc. (Darmstadt, Germany). The RIA kits for
insulin determination were obtained from Diagnostika (Falkenberg,
Sweden).
In vivo studies
Young adult GK and Wistar rats, 1–2 months of age, were
injected iv with glucose (11.1 mmol/kg), and serial blood sampling by
the retrobulbar approach was performed as previously described (20).
The volume load was 5 µl/g rat. Concentrations of insulin and glucose
in plasma were determined by the methods of Heding (21) and Bruss and
Black (22), respectively. To elucidate whether normalization of blood
glucose levels in the GK rat would affect islet lysosomal enzyme
activities, one group of GK rats was injected with phlorizin, and
another group was injected with solvent (propylene glycol). Phlorizin
(0.4 g/kg BW·day), made up as a 20% solution in propylene glycol, or
propylene glycol alone was administered as a sc injection every morning
and afternoon for 9 days. Wistar control rats receiving solvent were
included. Islets were then isolated as described below.
Islet studies
Young adult GK and Wistar rats were killed by decapitation and
immediately subjected to a retrograde injection of a collagenase
solution via the bile-pancreatic duct for preparation of isolated
pancreatic islets (23). The freshly isolated islets were either
collected for lysosomal enzyme analysis or used for insulin secretion
studies. For determination of lysosomal enzyme activities, 150–200
islets were thoroughly washed in glucose-free Hanks’ solution and
collected and stored in 300–400 µl acetate-EDTA buffer (1.1
mmol/liter EDTA and 5 mmol/liter acetate, pH 5.0) at -20 C. After
thawing in an ice bath and subsequent sonification, the islet
homogenates were analyzed for enzyme activities. Cathepsin D (pH 4.0)
was assayed with a slightly modified scaled down version of the method
of Barrett (24). The procedure for determination of acid phosphatase
(pH 4.5), acid -glucosidase (pH 4.0), ß-glucuronidase (pH 4.0),
N-acetyl-ß-D-glucosaminidase (pH
5.0), and neutral -glucosidase (pH 6.5) (endoplasmic reticulum) with
methylumbelliferyl-coupled substrates has previously been described
(3). Glucan-1,4--glucosidase activity with glycogen as substrate was
determined at pH 4.0 as previously described in detail (5, 25). Protein
was analyzed according to the method of Lowry et al.. (26).
Extraction and assay of islet insulin content were performed with
acid-ethanol as previously described (21, 27).
For insulin secretion studies, freshly isolated islets were preincubated for 30 min at 37 C in Krebs-Ringer bicarbonate buffer, pH 7.4, supplemented with 10 mmol/liter HEPES, 0.2% BSA, and 3.3 mmol/liter glucose as previously described (18). After preincubation (30 min), the buffer was changed to a medium of the same composition supplemented with the different test agents, and the islets were incubated for 60 min. All incubations were performed at 37 C in an incubation box (30 cycles/min). Each incubation vial was gassed with 95% O2 and 5% CO2 to obtain constant pH and oxygenation. Immediately after incubation, an aliquot of the medium was removed for assay of insulin (21). In the experiments with acarbose, islets were preincubated (with or without acarbose) for 60 min (to allow for acarbose uptake) at 1 mmol/liter glucose (9). After preincubation, the buffer was changed to a medium containing 1 or 16.7 mmol/liter glucose with or without acarbose, and the islets were incubated for 60 min unless otherwise stated (9).
Determination of lysosomal enzyme activities and neutral
-glucosidase in liver tissue
Liver specimens were homogenized in an acetate-EDTA buffer as
described above to yield a 2% liver homogenate. Assays of acid
phosphatase (pH 4.5), ß-glucuronidase (pH 5.0),
N-acetyl-ß-D-glucosaminidase (pH
5.0), and acid (pH 4.0) and neutral (pH 6.5) -glucosidase were
performed with methylumbelliferyl-coupled substrates as previously
described (3). The procedures for determination of acid
glucan-1,4--glucosidase at pH 4.0 with glycogen as substrate and of
cathepsin D at pH 4.0 with hemoglobin as substrate have been described
previously (3). Protein was determined with the Lowry method (26).
Statistics
Levels of significance between sets of data were assessed using
Student’s t test for unpaired data or, where applicable,
ANOVA followed by Tukey-Kramer’s multiple comparisons test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(upper
panel) shows that glucose-induced insulin secretion was greatly
impaired in the GK rats. In fact, the glucose injection did not
stimulate insulin release; instead, it brought about a significant
decrease in basal insulin levels at 15 min (P <
0.001). This strong impairment of insulin release in the GK rat was
reflected in a marked deterioration of the glucose tolerance curve in
these rats (Fig. 1, lower panel). It should be noted that
the basal plasma glucose levels (at time zero) were significantly
increased in GK rats compared with those in Wistar control rats,
whereas no difference was recorded with regard to the basal plasma
insulin levels.
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shows the effects of low
(3.3 mmol/liter) and high (16.7 mmol/liter) glucose on insulin
secretion from isolated islets of GK rats and Wistar control rats. It
is seen that insulin secretion at low glucose (3.3 mmol/liter) was of
similar magnitude in GK and Wistar islets. At high glucose, however,
the Wistar control islets released almost 3 times more insulin than the
GK islets during the 60-min incubation period. It is worth noting that
in contrast to the absence of a significant insulin-releasing effect in
the in vivo situation, the isolated GK islets responded to
glucose stimulation in vitro by a slight, but significant,
increase in insulin release (3.3 mmol/liter glucose, 0.30 ± 0.05
ng/islet·h vs. 16.7 mmol/liter glucose, 0.57 ± 0.08
ng/islet·h; P < 0.05). The addition of the adenylate
cyclase activator forskolin to the incubation medium in the presence of
16.7 mmol/liter glucose dramatically increased insulin release from
both Wistar and GK islets to the same level (Fig. 2).
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The GK rats displayed markedly increased plasma glucose concentrations,
whereas the plasma insulin levels were similar in GK rats and Wistar
controls. The islet insulin content was approximately 5.5 nmol/mg
protein (60 ng insulin/islet) in both categories of rats. Figure 3 shows that compared with Wistar control
rats, islets isolated from GK rats displayed decreased activities of
the lysosomal enzymes acid phosphatase (-33%),
N-acetyl-ß-D-glucosaminidase
(-25%), cathepsin D (-18%), and ß-glucuronidase (-20%), whereas
the activities of the two -1,4-splitting glucoside hydrolases, acid
glucan-1,4--glucosidase (+44%) and acid -glucosidase (+37%),
were increased. The activity of the neutral -glucosidase (an enzyme
attributed to the endoplasmic reticulum) was of the same magnitude in
islets from GK and control rats.
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shows the activities of the
different lysosomal enzymes and the neutral -glucosidase recorded in
liver tissue from control and GK rats. The liver lysosomal enzyme
activities displayed a pattern different from that of the islet
enzymes. Thus, the activities of the -1,4-splitting glucoside
hydrolases were of similar magnitude in control and GK rats. The only
significant difference with regard to lysosomal enzyme activities was
recorded with ß-glucuronidase, which was about 35% lower in the GK
liver.
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. Phlorizin treatment, in contrast to
its normalizing effect on plasma glucose levels, did not normalize the
different lysosomal enzyme activities in islet tissue of the GK rats.
Figure 5 also shows that similar to the results obtained in the
previous experiment (Fig. 3
), the activities of acid
glucan-1,4--glucosidase and -glucosidase were markedly enhanced
in GK rats compared with those in the Wistar controls, whereas the acid
phosphatase and
N-acetyl-ß-D-glucosaminidase
activities were again suppressed. The neutral -glucosidase activity
was of similar magnitude in all groups.
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-glucosidase
inhibitor acarbose shows the
dose-response relationship for the effect of acarbose on
lysosomal enzyme activities in islet homogenates as well as the effect
on glucose-induced insulin release. Acid glucan-1,4--glucosidase and
acid -glucosidase activities were dose dependently inhibited by
acarbose in islet homogenates from both Wistar and GK rats
(Fig. 6, A and C), suggesting that the catalytic activities of the
-glucosidehydrolases in GK islet homogenates were unaffected. Other
lysosomal enzyme activities in GK and Wistar islets were not influenced
by acarbose, as expected. Neutral -glucosidase activity
in islet homogenates was reduced at high concentrations of
acarbose. Similar to the effects of acarbose
on islet acid -glucosidehydrolase activities, the glucose-stimulated
insulin release from islets of Wistar controls was dose dependently
suppressed by the pseudotetrasaccharide (Fig. 6B), whereas insulin
release from GK islets was totally unaffected (Fig. 6D).
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and 8
show that acarbose inhibited acid
glucan-1,4--glucosidase activity at both low (modestly; Fig. 7A) and
high (markedly; Fig. 8A) glucose in islets from Wistar control rats.
Acid -glucosidase activity was inhibited only at high glucose (Figs. 7C and 8C). In contrast, no effects of acarbose were
observed on acid -glucosidehydrolase activities in islets from GK
rats (Fig. 7, A and C, and Fig. 8, A and C) suggesting that the
lysosomal/vacuolar system itself, and not the acid
-glucosidehydrolase enzyme activities, was impaired. Other lysosomal
enzyme activities or neutral -glucosidase in Wistar or GK islets
were not affected by acarbose (Fig. 7, D–F, and Fig. 8, D–F). Moreover, glucose-induced insulin release from GK islets was
totally unaffected by this high concentration of acarbose,
whereas glucose-induced insulin release from Wistar islets was severely
impaired (Fig. 8B). Basal insulin release at low glucose was slightly
inhibited by acarbose in Wistar islets, but was unaffected
in GK islets (Fig. 7B). Finally, it should be noted that in accordance
with the pattern of lysosomal enzyme activities in GK islets isolated
directly ex vivo (Figs. 3 and 6), the present enzyme
activities assayed in homogenates after incubation of intact islets
in vitro also displayed increased acid
-glucosidehydrolase activities and decreased activities of other
lysosomal enzymes at both low (Fig. 7) and high (Fig. 8) glucose
compared with Wistar control islets.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In agreement with a previous study, forskolin greatly potentiated
glucose-stimulated insulin release in normal Wistar islets and restored
the glucose-induced insulin release in GK islets (30). Interestingly,
forskolin was recently shown to overcome or compensate for the
inhibitory action of emiglitate, a selective -glucosidehydrolase
inhibitor, on glucose-stimulated insulin secretion from isolated mouse
islets (10). Hence, these data suggested that suppression of islet acid
glucan-1,4--glucosidase activity and thus glucose-induced insulin
release could be compensated for by a strong increase in the activity
of the cAMP system. The present forskolin data also suggest that the
exocytotic machinery per se in the GK islets is apparently
unaffected.
The physiological significance of the lysosomal glycogenolytic
hydrolases (acid -glucosidehydrolases) in pancreatic ß-cells is
largely unknown. As mentioned above, previous studies (3, 4, 5, 6, 7, 8, 9, 12, 13, 14, 19) have disclosed an apparent relation between islet acid
glucan-1,4--glucosidase activity and the insulin secretory response
to glucose, but not to insulin-releasing agents, acting via direct
stimulation of the adenylate cyclase and phospholipase C systems. In
the present investigation we observed that the islets of the diabetic
GK rat displayed significant abnormalities with regard to lysosomal
enzyme activities both when assayed directly ex vivo and
when analyzed after in vitro incubation of intact islets.
Thus, the activities of acid glucan-1,4--glucosidase and acid
-glucosidase were markedly increased, whereas the activities of
other lysosomal enzymes, such as acid phosphatase,
N-acetyl-ß-D-glucosaminidase,
cathepsin D, and ß-glucuronidase, were modestly decreased. It is
possible that the intensity and duration of the hyperglycemia in our
young GK rats could be of relevance for the elevation of the activities
of the acid glucan-1,4--glucosidase and acid -glucosidase,
because hyperglycemia can be detected by the age of 1 week (31). As
glucose utilization was shown to be 2- to 3-fold increased in GK rat
islets (18, 32, 33), and exposure of isolated islets to high glucose
in vitro augments the activity of acid lysosomal
-glucosidehydrolases (6, 7), it seems likely that the hyperglycemia
itself and/or the increased rate of glycolysis are conceivable
mechanisms contributing to the enhanced levels of the acid
-glucosidehydrolase activities in GK islets, although other
mechanisms cannot be ruled out. However, not even an apparent
normalization of the plasma glucose levels in the GK rat by phlorizin
treatment for 9 days changed the elevated acid
glucan-1,4--glucosidase activity. This is in accordance with our
earlier observation that old, previously hyperglycemic,
ob/ob mice that spontaneously returned close to normal
plasma glucose levels still displayed markedly elevated levels of islet
acid glucan-1,4--glucosidase activity (3, 13). However, in contrast
to the GK rat, the ob/ob mouse did not display any abnormal
function of the islet lysosomal system as such, as the elevated enzyme
activity in this animal still correlated with the markedly increased
plasma insulin levels (3, 13). Hence, although the islet acid
glucan-1,4--glucosidase is significantly increased in the GK rat, it
apparently is not given access to its substrate and consequently cannot
exert its in vivo catalytic activity and mediate appropriate
signaling in the glucose stimulus-secretion coupling. Therefore, it
seems possible that it is not the enzyme itself but, rather, a
malfunctioning lysosomal/vacuolar system as such that is an important
and decisive feature of the impairment of glucose-induced insulin
release in these rats. Further, the reduced activities of other
lysosomal enzymes in the islets of the GK rat are also suggestive of an
impaired function and activity of the whole lysosomal/vacuolar system.
In contrast, the hepatic lysosomal enzyme activities, except
ß-glucuronidase, were not different from those in the control Wistar
rats. The putative importance of the acid -glucosidehydrolases in
islet tissue is further underlined by the observation that in the
control rats, the specific activities of islet acid
glucan-1,4--glucosidase and acid -glucosidase were approximately
15-fold higher than those in the liver, whereas all other enzyme
activities were of generally the same magnitude in both islet and liver
tissue. It should also be noted that the present finding of decreased
activities of most lysosomal enzymes in the islets of our young GK rats
is probably not a sign of catabolic and degenerative processes in these
islets, as it is well known that degenerative changes in other tissues
bring about increased levels of classical lysosomal enzyme activities,
such as acid phosphatase, cathepsin D, and
N-acetyl-ß-D-glucosaminidase (34).
Moreover, in our young GK rats the islet content of insulin is normal
(cf. Table 1), and the morphological appearance of the
islets is not different from that in normal control rats (35).
Finally, our data from the acarbose experiments provide
further evidence to assume that in GK islets, it is not the
-glucosidehydrolase activity per se, but the whole
lysosomal/vacuolar system that is malfunctioning. We have previously
shown (9) that the pseudotetrasaccharide acarbose, a
potent inhibitor of islet acid -glucosidehydrolase (9), when
incubated together with mouse islets was taken up and exerted a strong
inhibitory effect on both acid glucan-1,4--glucosidase activity and
glucose-induced insulin release. In contrast, the tetrasaccharide
maltotetraos, which is devoid of inhibitory properties and is a close
analog of acarbose, did not affect either parameter (9).
Additionally, preliminary in vitro experiments in our
laboratory have shown that changes in glucose-stimulated insulin
secretion and enzyme activities induced by -glucosidehydrolase
inhibition correlate temporally. The present data further revealed that
with Wistar control islets the inhibition curve for glucose-stimulated
insulin release in the presence of acarbose was dose
dependent and similar in shape to the inhibition curve for acid
glucan-1,4--glucosidase activity. However, it should be noted that
the inhibition curve for insulin release was somewhat shifted to the
left compared with the enzyme inhibition curve. These data speak in
favor of a specific action of acarbose exerted on the acid
glucan-1,4--glucosidase activity within the vacuolar system in the
intact Wistar islets, as the concentration of an endocytosed compound
such as acarbose, which is restrained within the vacuolar
system, is always greater than that of a uniformly distributed compound
(36). In contrast, no inhibitory effect by acarbose was
recorded in intact, incubated islets from GK rats, showing that
acarbose was not given access to its target, the acidic
vacuolar compartment, in the ß-cells. Moreover, our observation that
the catalytic activities of acid glucan-1,4--glucosidase and acid
-glucosidase were suppressed to the same extent after direct
addition of acarbose to islet homogenates of both GK and
Wistar rats strongly speaks against a defect in acid
glucan-1,4--glucosidase activity itself. An impaired function of the
whole lysosomal/vacuolar system in intact GK islets is further
underlined by the fact that no sign of an acarbose effect
on -glucosidehydrolase activities or insulin secretion was seen even
if we used an extremely high concentration of acarbose (10
mM) in some experiments. Accordingly, as the catalytic
activities of the -glucosidehydrolases in GK islet homogenates
indeed are not impaired, one would have expected, similar to the
results of the Wistar control experiments, a clear and significant
inhibitory action by acarbose on both of these enzyme
activities as well as on glucose-induced insulin release in intact,
incubated GK islets if the lysosomal/vacuolar system had been operating
in a proper way. Hence, the intimate details of the pathophysiological
mechanisms behind the dysfunction of the lysosomal/vacuolar system in
the GK islets will await further investigations. Moreover, whether this
dysfunction is somehow coupled to other previously reported defects in
GK islet metabolism and ionic channel regulation (18, 30, 31, 32, 33, 37, 38, 39)
has yet to be elucidated.
In conclusion, we have shown that the secretory response to glucose was
markedly impaired both in vivo and in isolated islets of the
young GK rat. The defective response to glucose, however, could be
compensated for in the presence of the adenylate cyclase activator
forskolin. Further, in the GK rat the lysosomal enzyme activities in
islet tissue (but not in liver tissue) showed an abnormal pattern,
which could not be corrected by 9 days of phlorizin treatment and an
apparent normalization of the plasma glucose levels. Moreover, the
lysosomal/vacuolar system in the GK islets was not accessible to the
pseudotetrasaccharide acarbose, suggesting a defective
interaction between different organelle constituents within the
vacuolar system. Whether this abnormality is a reflection of a general
dysfunction of essential lysosomal membrane components and/or a
deficiency of certain key factor(s) assisting lysosomal enzymes in
their catalytic function remains to be elucidated. From the present and
previous data, we therefore propose that the defective insulin response
to glucose in the GK rat involves an important dysfunction of the islet
lysosomal/vacuolar system, which prevents the acid
glucan-1,4--glucosidase from exerting its action, and not an
impairment of the acid glucan-1,4--glucosidase activity per
se.
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Acknowledgments |
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Footnotes |
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Received December 14, 1998.
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