CLIN. CHEM. 19/5, 447-452 (1973)
Serum Enzymes in Diabetes Mellitus
Francesco
Belt iore, Luigi Lo Vecchio,
and Elena Napoli
Serum enzymes that show changed activities
in diabetes mellitus can be divided into four groups: Group
I includes
some lysosomal
enzymes-f.3-glucuronidase N-acetyl-fl-glucosaminidase,
acid phosphatase,
and amylase-that
show increased
activity correlated with blood sugar concentration.
Because lysosomal enzymes as well as liver amylase show latency
and may be “activated”
by several
agents,
their
increased
activity
in the serum of diabetics
might
be a manifestation
of an activation
occurring
in
tissues. Group II includes alkaline phosphatase
and
trehalase,
which are increased
but not correlated
with blood sugar concentration.
Their enhanced activity may reflect tissue metabolic
disorders.
Group
Ill includes enzymes that increase in the postketotic
period almost regularly-phosphohexose
isomerase
-or
in only the most severe cases-aminotransferases and several dehydrogenases-because
of tissue damage caused by metabolic
and circulatory
alterations.
Cholinesterase,
on the other hand, is decreased.
Group IV includes any of the above-mentioned enzymes,
and still others, that may be more
active in diabetics with complications
such as hepatIc and renal involvement
and obesity.
In diabetes
mellitus,
several serum enzymes
have
been studied.
The data reported
are apparently
unrelated
and often conflicting.
However,
when they
are considered
together,
a general
scheme
may be
envisaged
that
provides
an understanding
of the
changes
seen in the activities
of the various enzymes.
The scope of this review is to present
and discuss
available
data on serum enzymes
in diabetes
mellitus set in such a scheme,
as well as to consider
some
special problems
concerning
particular
enzymes.
The serum enzymes
investigated
in diabetes
mellitus can be divided
into (1) enzymes
whose activity
is
usually
increased,
and (2) enzymes
whose activity
is
usually
normal,
but which may change
in special
conditions
and in some patients.
The first group, in
turn, may be divided
into (a) enzymes
whose serum
level is correlated
with the concentration
of blood
sugar, and (b) enzymes
that do not show such a correlation.
The second group may be divided
into (a)
enzymes
that change
in the postketotic
period,
and
(b) enzymes
whose activity
may increase
in diabetics
with
complications.
Therefore,
altogether,
four
groups of enzymes are to be considered
(Table 1).
From the 10 Clinics Medica Generale e Terapia Medica della
Universit#{224}
di Catania, Ospedale Garibaldi, 95123 Catania, Italy.
Received Jan. 22, 1973; accepted Feb. 27, 1973.
Enzymes of Group I
This group includes
3-glucuronidase,1
N-acetyl-glucosaminidase,
acid phosphatase,
and amylase,
and
is characterized
by the occurrence
of a correlation
of
enzyme
activity
with the blood sugar concentration,
and therefore,
approximately,
with the degree
of
metabolic
decompensation.
The observation
of an increased
serum activity
of
fl-glucuronidase
(1-5)
and N-acetyl-f3-glucosamin.
idase (4, 6) in diabetes
mellitus,
with higher values
in women than in men (1, 3-5), has been given conflicting interpretations.
Some workers
(1, 4) have regarded the enzyme
change as being linked to the diabetic
condition.
Others
(2, 3), on the grounds
of
some data (7, 8) showing
a correlation
between
the
activity
of these enzymes
and atherosclerotic
disease,
have postulated
that the increased
activity
is linked
to the increased
susceptibility
of diabetics
to atherosclerosis.
Because
3-glucuronidase
activity
increases
in hepatic
diseases
(9-11),
its increased
activity
in
diabetes
has been also ascribed
to underlying
liver
involvement
(12). Further
evidence
would
suggests
that
the serum
activity
of these
two enzymes
is
linked to both the diabetic
state (5, 6, 13) and the
presence
of vascular
lesions in either the small or
large vessels (5, 6). In fact, in severely decompensated diabetics
with various degrees of ketoacidosis
the
activity
of both enzymes
in serum is markedly
ele‘Trivial
and nonstandard
names used: -glucuronidase
is $-Dglucuronide
glucuronohydrolase,
EC 3.2.1.31;
N-acetyl-fl-glucosaminidase
is chitobiose
acetylaminodeoxyglucohydrolase,
EC
3.2.1.29;
acid phosphatase
is orthophosphoric
monoester
phosphohydrolase,
EC 3.1.3.2;
amylase
is a-1,4-glucan
4-glucanohydrolase, EC 3.2.1.1; alkaline phosphatase
is orthophosphoric
monoester phosphohydrolase,
EC 3.1.3.1; trehalase
is trehalose
1-glucohydrolase,
EC 3.2.1.28; glucose-6-phosphatase
is o-glucose-6-phosphate phosphohydrolase,
EC 3.1.3.9; fructose-1,6-diphosphatase
is
D-fructose-1,6-diphosphate
1-phosphohydrolase,
EC
3.1.3.11;
phosphohexose
isomerase
is D-glucose-6-phosphate
ketol-isomerase, EC 5.3.1.9; aspartate
aminotransferase
is L-aspartate:2-oxoglutarate
aminotransferase,
EC 2.6.1.1; alanine aminotransferase
is L-alanine:
2-oxoglutarate
aminotransferase,
EC 2.6.1.2; sorbitol
dehydrogenase
is L-iditol:NAD
oxidoreductase,
EC 1.1.1.14;
glutamate
dehydrogenase
is i.-glutamate
: NAD(P)
oxidoreductase,
deaminating,
EC 1.4.1.3;
isocitrate
dehydrogenase
is threo-D9isocitrate:NADP
oxidoreductase
(decarboxylating)
EC 1.1.1.42;
malate
dehydrogenase
is L-malate : NAD
oxidoreductase,
EC
1.1.1.37;
lactate dehydrogenase is L-lactate:NAD
oxidoreductase,
EC 1.1.1.27;
cholinesterase
is acylcholine
acyl-hydrolase,
EC
3.1.1.8;
aldolase
is fructose-1,6-diphosphate
n-glyceraldehyde-3phosphate-lyase,
EC 4.1.2.13;
arginase
is L-arglnine
ureohydrolase, EC 3.5.3.1; lipase is glycerol-ester
hydrolase,
EC 3.1.1.3; creatine
kinase
is adenosine
triphosphate:creatine
phospho-transferase, EC 2.7.3.2.
CLINICAL CHEMISTRY, Vol. 19, No. 5. 1973
447
Table 1. Classification of Changes in Serum Enzyme Activity in Diabetes Mellitus
Increased enzymes
Enzymes usually normal, which may change in the postketotic period or in diabetics with complications
Enzymes whose activity is correlated
with glycemia
(Group I)
Enzymes whose activity is moderately increased and not correlated with glycemia (Group II)
Enzymes that may change
in the post-ketotic period (Group III)#{176}
Enzymes that may increase
in diabetics with complications (Group IV)
Beta-glucuronidase
N-Acetyl-beta-glucosaminidase
Acid phosphatase
Amylase#{176}
Alkaline phosphatase
Trehalase
Phosphohexose isomerase
Aspartate aminotransferase
A lanine aminotransferase
Sorbitol dehydrogenase
Glutamate dehydrogenase
I socitrate dehydrogenase
Malate dehydrogenase
Lactate dehydrogenase
Cholinesterasec
Enzymes of group III
Aldolase
Creatine kinase
Arginase
Lipase
Cholinesterase
a Enzymes of group I, being correlated with glycemla, are increased during ketotic episodes, but rapidly return to normal with the normalization
cemlc level, while enzymes of group III remain elevated for some days in the postketotiC period.
Amylase elevation becomes appreciable only in severely decompensated diabetics.
C Cholinesterase
Is decreased in the postketotic period, in contrast to the other enzymes of this group.
vated, with an increase
of up to 283% for 3-glucuronidase and 140% for N-acetyl-3-glucosaminidase,
and
is clearly correlated
with blood sugar concentration,
so that it returns
promptly
toward normal
as metabolic compensation
is achieved
(13). This indicates
that the increased
activity
is linked to the condition
of diabetic
decompensation,
and not, as postulated
by some workers,
to a possible
presence
of liver involvement
(12) or to susceptibility
to atherosclerosis
(2, 3). This view is supported
by the normal activity
of other enzymes,
including
aspartate
and alanine
aminotransferases,
observed
in most instances
(13).
The correlation
with the degree of glucose metabolic
disorder
is also confirmed
by the statistically
significant correlation
between
enzyme
activity
and sugar
concentration
found
in large series of diabetics
for
both f3-glucuronidase
(5) and N-acetyl-fl-glucosaminidase (6). On the other hand,
the relationship
between the activity
of these enzymes
and the presence
of vascular
lesions, that previously
had been postulated on tenuous
grounds
(2), appears
to be substantiated by the correlation
of the higher enzyme activity observed
in diabetics
with disease
of either the
small or large blood vessels when compared
with the
activity
in uncomplicated
diabetics
with similar
degrees of hyperglycemia
(5, 6). This relationship
is
also indicated
by the finding that the correlation
of
fl-glucuronidase
and
N-acetyl-3-glucosaminidase
with blood sugar concentration,
present in uncomplicated diabetics,
does not occur in diabetics
with diseased blood vessels (5, 6). This shows that the presence of vascular
lesions is an interfering
factor that
may modify serum
enzyme
activity.
The failure of
some workers (2) to demonstrate
the correlation
of
serum
3.glucuronidase
with both the blood sugar
and vascular
lesions may perhaps
be attributed
to
the fact that the effect of the latter was not studied
in diabetics
with
similar
glucose
concentrations,
and the effect of hyperglycemia
was not studied
in
diabetics
without vascular
lesions.
448
CLINICAL CHEMISTRY, Vol. 19, No. 5, 1973
of gly-
Concerning
the correlation
with sugar concentration, it must
be pointed
out that experiments
in
which
j3-glucuronidase
and N-acetyl-3-glucosaminidase were assayed
before and after addition
of glucose to serum showed that glucose per se does not
affect the activity of these two enzymes (13).
Since 3-glucuronidase,
together
with N-acetyl-3glucosaminidase
and other enzymes,
is able to degrade mucopolysaccharides
and glycoproteins,
its increased
activity
in the serum of diabetics
has been
regarded
as a defense mechanism
against
accumulation of these compounds
in the walls of blood vessels
(2), as occurs in diabetics
with vascular
disorders.
However,
it has been pointed
out (5) that
this
hypothesis
can apply only for the enzyme change occurring in diabetics
with lesions of large vessels, but
not for those occurring
in diabetics
with disease
of
small vessels. In fact, unlike the walls of large blood
vessels, the basement
membrane
of small blood vessels, which is the site of diabetic
microangiopathic
lesion, does not contain
glucuronic
acid, but instead
glycoproteins,
constituted
of characteristic
carbohydrate units, made up of glucose-galactose
disaccharides (14). Based on the consideration
that both /glucuronidase
and N-acetyl-3-glucosaminidase
are
lysosomal
enzymes
(15), and that lysosomes
have
a rich complement
of hydrolytic
enzymes
capable
of degrading
a large
variety
of compounds,
the
hypothesis
has been put forward
(5, 6, 13) that the
increase
of
9-glucuronidase
and
N-acetyl-flglucosaminidase
in serum could be the expression
of
lysosome
involvement
in tissues,
leading
to activation
of lysosomal
hydrolases.
This
phenomenon
probably
occurs in response
to the metabolic
need to
degrade
any of these
compounds
that have accumulated
in tissues, such as mucopolysacchanides
and
glycoproteins
in diabetics
with vascular
disease
(5,
6), or various
constituents
of cells themselves,
in a
context
of increased
tissue catabolism,
as occurs in
diabetics
at a rate proportional
to the degree of met-
abolic decompensation
(13). Unpublished
data from
this laboratory
further
supports
this hypothesis,
for
it showed that also a third lysosomal
enzyme,
acid
phosphatase,
was increased
in 40 adult uncomplicated diabetics,
with a mean increase
of 148%, statistically significant
(P <0.01).
The observation
that in experimental
activation
of
lysosomes,
lysosomal
enzymes
are released from cells
(16) and increase
in serum (17, 18) has been regarded (5, 6, 13) as supporting
the hypothesis
described
above.
As far as serum amylase
is concerned,
some workers (19-22) have found decreased
activity
in diabetes, others (23-29)
a normal
activity,
others
(30)
variable
values,
and still others
(31, 32) increased
activity
in untreated
diabetics
and normal values in
diabetics
receiving
insulin.
Furthermore,
a definitely
lowered activity
has been reported
in cases of diabetic coma (21, 22), and this diminished
amylase
activity has been regarded
as an index of liver involvement
(21, 22).
A series of reports have dealt with the relationship
between
blood amylase
and carbohydrate
metabolism (33-35),
or hormones
that affect carbohydrate
metabolism
(35-37),
and have
given
rise to the
suggestion
that blood amylase
is affected
by the anterior pituitary
(36) and by ACTH
or cortisol
(35,
37), and that “plasma
amylase
falls during states of
increased
carbohydrate
utilization,
and rises following the administration
of hormones
that diminish
utilization
of carbohydrate
or in physiological
states
of diminished
carbohydrate
utilization
as when
insulin
is withheld
in patients
with diabetes”
(38).
Based on these statements,
an increased
serum amylase activity
should be expected
in decompensated
diabetes.
Indeed,
several tudies
reporting
decreased
serum
amylase
activity
in decompensated
diabetes
(21, 22)
are perhaps
invalidated
by the demonstration
that
determination
of amylase
activity
by unmodified
Somogyi
saccharogenic
methods
gives falsely
low
values because
of the interference
of glucose, so that
the higher the glucose concentration,
the lower will
be the amylase
value obtained
(29). Actually,
when
amylase
activity
is determined
by the amyloclastic
method,
which
avoids
this interference
(29), the
values found
in diabetics
are normal
(29). Studies
from this laboratory
(39) are in agreement
with this
finding,
having shown a value of 127 (±51) Somogyi
units/100
ml of serum in 75 diabetics,
and of 124 ±
38 units in 60 normal
subjects.
In severely
decompensated
diabetics
with ketoacidosis,
on the other
hand, serum amylase
activity
is markedly
elevated
(39-41),
and is accompanied
by increased
urinary
excretion
of the enzyme
(39, 41). This latter finding
allows
us to exclude
the possibility
that
the increased
activity
in serum is the result of impairment
in renal excretory
function,
which is often present in
diabetic
ketoacidosis.
Furthermore,
the enzyme
activity
is correlated
with blood glucose,
so that the
values
return
to normal
with the normalization
of
.
.
.
the blood sugar (39). No definite
explanation
has
been given for either the source of serum amylase
or
the mechanism
of its elevation
in diabetic
coma. A
correlation
has been observed
between
the increased
serum amylase
activity
and dehydration
(40) or plasma hyperosmolarity
(41), but the nature of these relationships
remains
obscure.
The pancreatic
origin of
the serum enzyme has been excluded
because
of the
absence
of pancreatic
lesions at the postmortem
examination
(40) and the normality
of serum
lipase
(39, 41). A release
of amylase
from liver cells has
been postulated
(40). Since it has been observed
that
the behavior
of amylase
in the serum
of diabetics
with ketoacidosis
is closely correlated
with that of
some lysosomal
enzymes
such as fl-glucuronidase,
N-acety1-3-glucosaminidase,
and acid phosphatase,
it has been suggested
that
a similar
mechanism
could be responsible
for the change in both amylase
and lysosomal
enzymes
(39).
Liver amylase,
although
located
primarily
in microsomes,
is present
in a “latency”
state and is activated by some agents (42) as are lysosomal
enzymes.
Therefore,
it has been hypothesized
(39) that, as for
lysosomal
enzymes,
the increased
serum amylase
activity might reflect an activation
occurring
in liver
tissue in diabetic
ketoacidosis.
Possibly
liver microsomes are less affected
than lysosomes
by the diabetic state.
This could
explain
why serum
amylase
changes
appreciably
only in severely decompensated
diabetes
with ketoacidosis,
in contrast
to lysosomal
enzymes,
whose level is significantly
increased
also
in nonketotic
diabetics,
as described
above.
Enzymes of Group II
This group includes
alkaline
phosphatase
and trehalase.
The activity
of these two enzymes
is moderately increased
in diabetes,
and does not show correlation with the blood glucose.
Alkaline
phosphatase
activity
has been found elevated by 40% (P < 0.001), with a frequency
of increased values of 44%, in a series of 166 uncomplicated diabetics
(43). Enzyme
activity
was correlated
with the daily insulin
requirement
(r = 0.263; P <
0.05), but not with the glucose concentration
or the
known duration
of disease (43). The enhanced
activity of this enzyme has been tentatively
interpreted
as
a manifestation
in serum of the increased
phosphatase activity
that may occur in tissues in the diabetic
state. In this condition,
increased
activity
has been
reported
for glucose-6-phosphatase
(44, 45) and fructose-1,6-diphosphatase
(46) in the liver. These phosphatases
are enzymes
distinct
from alkaline
phosphatase
(47). However,
owing to some overlapping
substrate
specificity
shown
by the phosphatases
under consideration
(47), and the possibility
that an
enhanced
alkaline
phosphatase
might be present
in
tissues of diabetics,
it cannot be excluded
that phosphatases
released
from tissues,
mainly
liver, might
contribute
to the elevated
serum alkaline
phosphatase activity
(43). Further
studies
are needed
for a
better
characterization
of serum
alkaline
phosphaCLINICAL
CHEMISTRY,
Vol. 19. No. 5. 1973
449
tase in diabetes
before a more precise interpretation
of this enzymatic
change can be given.
Concerning
trehalase,
the increased
activity
reported in serum of diabetics
(48), with no significant
correlation
with blood glucose concentration
or years
since diagnosis,
has been connected
with the postulated role (49) of this enzyme
in carbohydrate
metabolism.
In fact,
this membrane-bound
enzyme,
which hydrolytically
splits the disaccharide
trehalose
into two glucose moieties,
might function,
in concert
with the enzymes
that convert
glucose to trehalose,
in the active transport
of glucose from the glomerulan filtrate
and across the intestinal
mucosa
(49). As
serum
trehalase
activity
shows
large intersubject
variability
on a genetic
basis, it has been suggested
that the elevated
plasma trehalase
activity
might be
either an effect of diabetes
or an index of increased
susceptibility
to it (48).
Enzymes of Group III
This group includes
several serum enzyme
activities (Table 1) that may change in the postketotic
period. Phosphohexose
isomerase
activity
is increased
in almost
all instances.
In fact, in our series of 16
cases of diabetes
with ketoacidosis
(unpublished
observations),
activity
was augmented
in the serum of
all the subjects
but one. The increased
activity
of
this enzyme
might be regarded
as a result of diffuse
tissue damage
caused by the complex
metabolic
disorder occurring
in diabetic
ketoacidosis.
Actually,
owing to the high activity
of this enzyme
in most
tissues, it is probable
that damage
even of a mild degree, but spread over most organs,
may give rise to
an appreciable
serum
enzyme
elevation.
This assumption
is in keeping
with the observation
that an
increased
serum activity
of phosphohexose
isomerase
is present
(50) in cases of cardiac failure and of bronchial asthma
with severe anoxia, probably
because of
generalized
metabolic
abnormalities.
Other enzymes
of this group-such
as aspartate
and alanine
aminotransferases,
sorbitol-,
glutamate-,
isocitrate-,
malateand lactate
dehydrogenases-were
increased
only in some instances
in our series, mainly
in the
most severely ill patients,
especially
when circulatory
failure
was severe and the liver was markedly
enlarged.
This suggests
that liver damage,
primarily
caused by congestion
and metabolic
disorder,
might
be the cause of these enzymatic
changes.
The inconstant occurrence
of increased
lactate
dehydrogenase
activity
in diabetic
ketoacidosis
may explain why, in
small series of patients,
either increased
activity
(51)
or normal
values
(52) have been observed.
As concerns serum
aminotransferase
activity,
it must be
mentioned
that only findings
obtained
by using kinetic methods
with appropriate
controls
are reliable
in diabetic
ketosis,
because
in this condition,
when
measurement
is made
by multi-channel
chemical
analysis,
there is interference
from acetoacetate
(53),
which may be responsible
for the apparent
elevation
of aminotransferase
activity
reported
by some workers (54).
450
CLINICAL
CHEMISTRY,
Vol. 19, No.5,
1973
Serum cholinesterase
is unique because
its level is
decreased
2-3 days after episodes
of ketoacidosis
(55). Since
activity
of this enzyme
decreases
in
serum in cases with liver involvement
(56), damage
to this organ again seems the most probable
cause of
this enzyme
change.
As already
described,
in ketoacidotic
patients
there is also an elevation
of the enzymes of group I. However,
as shown in Figure 1, the
peak activity
of enzymes
of group I is simultaneous
to the peak of hyperglycemia,
and the activity
rapidly returns
to normal
with the normalization
of glucose concentration,
while the peak of enzyme
activities of group III is delayed
compared
to that of the
glucose,
and persists
for some days during the postketotic
period,
when metabolic
compensation
is already achieved.
This would indicate
that while the
enzyme
activities
of group I are correlated
with the
degree of metabolic
decompensation,
the changes
in
enzymes
of group III are rather the expression
of tissue damage
consequent
to the establishment
of diabetic ketoacidosis.
Enzymes of Group IV
This group includes
a number
of enzymes
(Table
1) that are usually
normal
in diabetic
patients,
but
that may increase
in some instances
as manifestation
of complications
of the diabetic
disease.
The most
common
causes
of increased
activity
of these enzymes
in diabetic
patients
are liver or kidney
involvement
and obesity.
In relatively
large series of
patients,
comprised
of 200 (57) and of 130 (58)
subjects,
increased
serum enzyme
activity,
regarded
as an index of liver damage,
was reported
for aspartate and alanine aminotransferases
(57, 58), sorbitol-,
glutamate-,
and isocitrate
dehydrogenases,
and arginase (58). The frequency
of elevation
is different
for the various enzymes
and reports.
In some reports
(59) normal activities
of both aminotransferases
have
been found in all instances
and enhanced
activity
of
lactate
dehydrogenase
in some patients.
The incidence of enzyme change probably
reflects merely the
frequency
and severity
of liver involvement
in the
series of patients
studied.
Other enzymes-such
as
phosphohexose
isomerase,
malate dehydrogenase
and
lipase-were
found to be almost always normal
(unpublished
observation),2
and the same was true for
serum creatine
kinase (60). In an earlier work (61), a
marked
elevation
of phosphohexose
isomerase
had
been reported
in eight of nine diabetics.
However,
since in that paper the clinical condition
of the diabetics studied
was not described,
it cannot be excluded
that they were decompensated
diabetics
with some
degree of ketoacidosis,
a condition
that almost regularly gives rise to elevation
of phosphohexose
isomerase activity,
as described
under Enzymes
of Group
III. Concerning
renal involvement,
some workers (62)
2
Values observed
(mean
±SD):
27 ± 12 U/liter
in 130 diabetics
and 28 ± 11 U/liter
in 70 normals
for phosphohexose
isomerase;
74 ± 39 U/liter
in 137 diabetics
and 67 ± 20 U/liter
in 50 normals
for malate
dehydrogenase;
3.51 ± 1.32 U/liter
in 40 diabetics
and
3.37 ± 1.24 U/liter
in 40 normals
for lipase. The difference
in the
activity
between
normals
and diabetics
was not statistically
significant
for these
three
enzyme
activities,
the P value
being
>0.30.
7
Fig. 1. Behavior of four representative
serum enzyme
activities (lines 1-4) and of
blood glucose (line 5) in a
diabetic patient with severe
metabolic
decompensation
and ketoacidosis
6
D
5.
4.
Line 1 refers to $-glucuronidase,
which is representative of a group of
enzymes that are increased in diabetes and correlated with glycemia;
line 2 refers to alkaline phosphatase, which is representative
of a
group of enzymes that are moderately increased In diabetes and not
correlated with glycemia; line 3 refers to phosphohexose
isomerase,
which Is representative of a group of
enzymes that are increased in the
postketotlc period; line 4 refers to
aspartate aminotransferase,
which
is representative of a group of enzymes that may increase in diabetes
with complications
(I)
S
F
3.
2
F
o
5
o
0
612
Hours
24
prom
the
4’8
3’6
Onset
o
mental
&O
have described
increased
serum activity
of phosphohexose isomerase,
aspartate
and alanine aminotransferases,
and lactate
dehydrogenase
in diabetics
with
this complication.
The same enzymatic
changes were
observed
in diabetics
with obesity
(62). This last
condition
has been held responsible
also for the increased serum cholinesterase
activity (59, 63). The activity of this enzyme, in fact, is increased
only in those
diabetics
who are overweight,
suggesting
that the elevation
is associated
with the accompanying
obesity
rather than with the diabetes
itself (63).
Summary
From the data reviewed above we deduce that several serum enzymes
may change in diabetes
mellitus.
The increase
of some of these enzymes
(groups I and
II) seems closely related
to the diabetic
metabolic
alterations,
while
the change
of other
enzymes
(groups III and IV) are only indirectly
related
to diabetes, being expression
of either acute tissue damage
caused
by
episodes
of severe
decompensation
(changes
of enzymes
of group III), or complications
that may develop
during the chronic
course of diabetic disease (increase
of enzymes of group IV).
We are greatly indebted to Saverio Signorelli,
M.D., Professor
and Chairman,
Department
of Medicine,
University
of Catania
Medical
School, and Head of the Postgraduate
School of Hem atologic and Metabolic
Diseases,
for having
supported
the studies
from this laboratory
that have been cited in this review.
References
1. Hagenfeldt,
L., and Wahlberg,
F., Serum
beta-glucuronidase,
glucose
tolerance,
and
atherosclerotic
disease.
Lancet
1, 788
(1965).
2. Miller,
B. F., Keyes,
F. P., and Curreri,
P. W., Increase
of
serum beta-glucuronidase
activity
in human
diabetes
mellitus.
J.
Amer. Med. Ass. 195, 189(1966).
3. Jim#{234}nez,J. A., Cole, H. S., and Camerini-Dbvalos,
R. A., Aumento
de la actividad
de Ia beta-glucuronidasa
del suero en Ia
diabetes
quimica.
Acta Diabetol.
Lot. 6, 523 (1969).
4. Woollen,
J. W., and Turner,
P.,
glucose
tolerance,
and atherosclerotic
(1965).
84
108
cloudiag
Serum
beta-glucuronidase,
disease.
Lancet
i, 1071
5.
Belfiore,
F., Lo Vecchio,
L., and Napoli, E., Serum beta-glucuronidase
activity
in diabetic
patients,
as related
to vascular
complications
and degree
of glucose
metabolic
disorder.
Amer.
J.
Med. Sci. 264, 457 (1972).
6. Belfiore,
F., Napoli,
E., and Lo Vecchio,
L., Serum N-acetylbeta-glucosaminidase
activity
in diabetic
patients.
Diabetes
21,
1168(1972).
7. Miller,
B. F., Keyes, F. P., and Curreri,
P. W., Serum betaglucuronidase
activity
of various species: Possible
correlation
with
susceptibility
to atherosclerosis.
Proc. Soc. Exp. Biol. Med. 119,
1129(1965).
8. Miller, B. F., Keyes, F. P., and Curreri,
P. W., Increased
tivity of serum beta-glucuronidase
in patients
with coronary
tery disease. J. Atheroscier. Res. 7,591(1967).
acar-
9. Rutenburg,
A. M., Pineda,
E. P., Banks, B. M., and Goldbarg,
J. A., Clinical
interpretation
of serum beta-glucuronidase
activity.Amer.
J. Dig. Dis. 8,789(1963).
10. Jedrychowski,
A.,
and
Drozdz,
#{149}
blood
serum
beta-glucuronidase
parenchymatous
liver injury.
(1969). (In Polish).
11. Nilius,
R.,
Berucksichtigung
au. Stoffwechselkr.
H.,
and
Diagn.
Comparative
studies
amino-transferases
Lab.
(Warszawa)
Leberverfettung
und Fettleber
der Serum Beta-Glukuronidase.
29,81(1969).
5,
on
in
367
unter
Besanderer
Deut. Z. Verd-
12. Nilius,
R., Krosch,
H., and Zipprich,
K.-W.,
Zur
nostischen
Aussagefahigkeit
der Serum-Beta-Glukuronidase.
Die Serum-Beta-Glukuronidase-Aktivitat
bei Arteriosklerose
Diabetes
mellitus.
Z. Inn. Med. 26, 393 (1971).
DiagIV.
und
13. Belfiore,
F., Napoli,
E., and Lo Vecchio, L., Increased
activity of some enzymes
in serum in cases of severely
decompensated
diabetes
with and without
ketoacidosis.
Clin. Chem. 18, 1403
(1972).
14. Beisswenger,
P. J., and Spiro,
R. G., Human
glomerular
basement
membrane:
Chemical
alteration
in diabetes
mellitus.
Science
168,596(1970).
15. Straus,
W., Lysosomes,
phagosomes
and related
particles.
In
Enzyme
Cytology,
D. B. Roodyn,
Ed. Academic
Press, New York,
N.Y., l967,p239.
16. Frimmer,
M., Gries, J., and Waldvogel,
G., Akute Wirkungen
hoher Dosen Vitamin
A (Alkohol,
Aldehyd
und Saure)
auf die
Stabilit#{228}tvon Lysosomen
in der perfundierten
Rattenleber.
Z.
Vitaminforsch.
38,454 (1968).
mt.
17. Weiasmann,
G., Uhr, J. W., and Thomas,
L., Acute hypervitaminosis
A in guinea
pigs. I. Effects
on acid hydrolases.
Proc.
Soc. Exp. Biol. Med. 112,284(1963).
18. Schmidt,
M., Dmochowski,
A., Laskowski,
S., and Czarnecki,
M., Biochemical
studies
on the physiological
role of lysosomes.
Pot. Tyg. Lek. 24, 224 (1969). (In Polish).
19. Lewis,
D. S., and Mason, F. H., The
44, 455 (1920).
diastatic
ferments
of the
blood. J. Biol. Chem.
CLINICAL
CHEMISTRY,
Vol. 19, No.5,
1973
451
20. Ottenstein,
und des Blutes
ische Bedeutung
(1931).
B., Untersuchungen
uber der Gehalt
der Haut
an diastatischen
Ferment
und dessen
biochimbei Hautkrankheiten.
Biochem.
Z. 240, 328
21. Gray, S. H., Probstein,
J. G., and Heifetz,
C. J., Clinical
studies on blood diastase:
I. Low diastase
as an index of impaired
hepatic function.
Arch. Intern. Med. 67,805(1941).
22. Somogyi,
M., Blood diastase
in health
and diabetes.
J. Biol.
Chem. 134,315(1940).
23. Benczur,
J. V., Beitrag zur Klinischen
Verwertharkeit
d#{233}r
Diastasemenge
in Blutserum
und Urin. Wien. Kim.
Wochenschr.
23,890(1910).
24. Milne,
L. S., and Peters,
H., Observations
on the glycolytic
power of the blood and tissues in normal and diabetic
conditions.
J. Res. 26, 412 (1912).
25. De Niord,
H. H., and Schereiner,
B. F., Diastatic
activity
of
the blood in cancer,
syphilis
and diabetes.
Arch. Intern. Med. 23,
484(1919).
26. Brill, I. C., Studies
on the diastatic
activity
of the blood, with
a consideration
of its value in clinical
diagnosis.
Arch. Intern.
Med. 34, 542(1924).
27. Von Strasser,
W., Untersuchungen
Uber das diastatische
Ferment in Blut. Deut. Arch. Kim. Med. 151, 110(1926).
28. Norby, G., The amylase
concentration
ics. Acta. Med. Scand.,
Suppi. 78,983(1936).
in the serum
of diabet-
29. Street,
H. V., Serum
amylase
activity:
Its determination
health and in diabetes
mellitus.
Ciin. Chim. Acta 3,501(1958).
30. Searcy,
R. L., and Dunn, J. M., Serum
betes mellitus.
Lancet ii, 373 (1961).
amylase
levels
in
in dia-
31. Myers, V. C.,
and Killian,
J. A., Studies
on animal diastases:
I. The increased
diastase
activity
of the blood in diabetes
and nephritis.J.
Biol. Chem. 29,179(1917).
32. Reid, E., and Myers, V. C., Studies
on animal
diastases:
IV.
The effect of insulin
on the diastatic
activity
of the blood in diabetes.J.
Biot. Chem. 99,607(1933).
33. Dreiling,
D. A., Janowitz,
H. D., Marshall,
D., and Haemmerli,
P., Relationship
between
blood amylase
and factors
affecting carbohydrate
metabolism.
I. The regulation
of blood amylase levels in subjects without pancreatic
disease.
Amer. J. Dig.
Dis. 3, 214 (1958).
34. Dreiling,
D. A., and Bierman,
E. L., Correlation
between
plasma
amylase
activity
and concentration
of plasma
non-esterifled fatty
acids
(NEFA).
Proc. Soc. Exp. Biot. Med.
95, 496
(1957).
35. Dreiling,
D. A., Rosenthal,
W. K., Kass, M., and Janowitz,
H. D., Relationship
between
blood amylase
and factors affecting
carbohydrate
metabolism.
II. The influence
of ACTH, hydrocortisone, liver disease and pancreatectomy.
Amer. J. Dig. Dis. 4, 731
(1959).
42. Brosemer,
lar distribution
R. W., and Rutter,
W. J., Liver amylase.
I. Celluand properties.
J. Biol. Chem. 236, 1253 (1961).
43. Belfiore,
F., Romeo,
F., Furn#{244},C., and Lo Vecchio,
L.,
L’attivitk
fosfatasica
alcalina
del siero nel diabete
mellito.
Metabolismo 4,359(1968).
44. Patrik,
S. J., and Tulloch,
J. A., Glucose-6-phosphatase
activity in human diabetes.
Lancet i, 811 (1957).
45. Egeli, E. S., and Alp, H., Die Glukose-6-Phosphatase-Aktivitat der Leber bei normalen
und bei Diabetikern.
Z. Kim.
155, 191 (1958).
Med.
46. Ritter,
P., Jenny,
E., Hicklin,
A., and Leuthardt,
F., Die
Aktivitat
der Fructose-1,6-diphosphat-1-Phosphatase
in der Leber
alloxandiabetischerRatten.
Helu. Physiol. Acta 19,234(1961).
47. Stadtman,
T. C., Alkaline
phosphatase.
P. D. Boyer, H. Lardy,
and K. Myrback,
New York, N.Y., 1961, p 35.
In The Enzymes,
5,
Ed. Academic
Press,
48. Elze, L. C., and Price Evans, D. A., Plasma
trehalase
in diabetes
mellitus.
Clin. Chim. Acta 28, 153(1970).
activity
49. Sacktor,
B., Trehalase
and the transport
of glucose
in the
mammalian
kidney and intestine.
Proc. Nat. A cad. Sci. U. S. 60,
1007 (1968).
50. West,
M., Gelb, D., Pilz, C. G., and Zimmerman,
H. J.,
Serum enzymes
in disease.
VII. Significance
of abnormal
serum
enzyme
levels in cardiac
failure.
Amer.
J. Med. Sci. 241, 350
(1961).
51. Wroblewski,
F., and La Due J. S., Lactic dehydrogenase
activity in blood. Proc. Soc. Exp. Biol. Med. 90,210(1955).
52. Hsieh, K. M., and Blumenthal,
H. T., Serum lactic dehydrogenase levels in various disease states. Proc. Soc. Exp. Biol. Med.
91,626(1956).
53. Chen, J. C., Marster,
R., and Wieland,
R. G., Diabetic
ketosis. Interpretation
of elevated
serum glutamic
oxalacetic
transaminase
(SGOT)
by multi-channel
chemical
analysis.
Diabetes
19,730(1970).
54. Cryer, P. E., and Daughaday,
W. H., Diabetic
ketosis:
Elevated serum glutamic
oxalacetic
transaminase
(SGOT)
and other
findings
determined
by multi-channel
chemical
analysis.
Diabetes 18, 781 (1969).
55. Maier,
Deut. Med.
E. H., Serumcholinesterase
Wochenschr.
81, 1674 (1956).
und
Lebererkrangungen.
56. Abderhalden,
R., Clinical
Enzymoiogy.
Van Nostrand
Inc.,
Princeton,
N. J., 1961, p 41.
57. Ozgu#{231},
L., and Duncan,
L. J. P., Serum glutamic
oxalacetic
and glutamic
pyruvic
transaminase
levels in diabetes
mellitus.
Clin. Chim. Acta 3,586(1963).
58. Belfiore,
F., Meldolesi,
J., and Calcara,
G., Comportamento
‘di alcune
attivitk
enzimatiche
nel siero di sangue
nel diabete
mellito,
con particolare
riferimento
agli enzimi
epatospeciflci.
Acta Diabetol.
Lot. 1, 164(1964).
36. Cope, 0., Hagerstimier,
A., and Blatt, M., The activity
of the
blood serum
amylase
in the hypophysectomized
dog. Amer.
J.
Physiol.
182,428(1938).
37. Pfeffer, R. E., and Hinton,
J. W., Some relationships
between
adrenal
medullary
and cortical
substances
and exocrine
secretion
of the pancreas.
Gastroenterology
31,746(1957).
59. Pelocchino,
A. M., Prinotti,
C., and Rigazio,
G., Attivit#{224}
transaminasiche,
latticodeidrogenasica
e pseudocolinesterasica
del siero nel diabete mellito. Arch. Sci. Med. 110,451(1960).
38. Janowitz,
H. D., and Dreiling,
D. A., The plasma
amylase.
Source,
regulation
and diagnostic
significance.
Amer. J. Med. 27,
924(1959).
61. Bruns, F. H., and Jacob, W., Studien
Uber Serumenzyme
Erkrangungen
der Leber. Die Aktivit#{228}tder Phosphohexoseisomerase, Aldolase
und alkalischen
Phosphatase.
Kim. Wochenschr.
1041 (1954).
39. Belflore,
F.,
lasemia in diabetic
40. Finn,
R.,
coma. Diabetes
and Napoli,
coma. Clin.
and Cope,
S.,
12, 141 (1963).
E., Interpretation
of hyperamyChem. 19, 387 (1973).
The
41. Azerad,
E., Lubetzki,
J., Duprey,
isier, G., L’amylasemie
au cours des
18,89(1970).
452
plasma
amylase
J., Croisier,
J.-C.,
comas diabetiques.
CLINICAL CHEMISTRY, Vol. 19, No. 5, 1973
in diabetic
and CroDiabkte
60. Belfiore,
F., Lo Vecchio.
L., Napoli,
E., and Di Stefano,
C.,
L’attivit#{224}creatina
cinasica
del siero in un gruppo
di diabetici.
Boll. Soc. Itai. Biol. Sper. 46, 379(1970).
bei
32,
62. Gray, G., Sorensen,
G. H., and Sorensen,
N. S., The activity
in serum of the enzymes
glutamic
oxalacetic
transaminase,
glutamic pyruvic
transaminase,
lactic dehydrogenase
and phosphohexose
isomerase
in diabetes
and obesity.
Rep. Steno Hosp.
(KBH) 11,195(1963).
63. Thompson,
R. H. S., and Trounce,
J. R., Serum cholinesterase levels in diabetes
mellitus.
Lancet i, 656(1956).