Tohoku
J. exp.
Med.,
1975,
Glucagon-Induced Diabetic Subjects
116, 103-110
Insulin
Secretion
in Normal
AKIRA OHNEDA, KIYOSHI MATSUDA, MASAMICHI YASUO IIMURA and SHOICHI YAMAGATA
and
CHIBA,
The Third Department of Internal Medicine, Tohoku University School of Medicine, Sendai
OHNEDA, A., MATSUDA, K., CHIBA, M., IIMURA, Y. and YAMAGATA,S. Glucagon-Induced Insulin Secretion in Normal and Diabetic Subjects. Tohoku J. exp. Med., 1975, 116 (2), 103-110 Eight normal subjects and ten diabetic patients were studied to compare the response of plasma insulin to glucagon with that to glucose and tolbutamide. Oral glucose tolerance test, glucagon test and tolbutamide-glucagon test were performed at intervals of several days. In glucose tolerance test, insulin response was reduced in the patients with severe diabetes. Plasma insulin increased and reached the peak 3 min after glucagon injection (glucagon I) in the normal controls, while plasma insulin response was reduced in diabetic patients, especially in the severe diabetics. In the normal controls plasma insulin rose and reached the peak 6 min after the tolbutamide injection and thereafter fell to the initial level. Glucagon injection following tolbutamide (glucagon II) caused the rise in insulin in the control subjects. In diabetics insulin response to either tolbutamide or glucagon 1 was reduced. Tolbutamide or glucagon II caused a significant difference in plasma insulin response in all the diabetic groups compared with the normal subjects, while glucose or glucagon I showed a significant increment of plasma insulin between the normal subjects and the severe diabetics. These results suggest that injection of tolbutamide as well as glucagon II provides a definite discrimination of insulin response in diabetics from the normal controls. The usefulness of the tolbutamide - glucagon test in the diagnosis of diabetes mellitus was discussed. glucose tolerance test; glucagon test; tolbutamide-glucagon test; plasma insulin
Since the development of radioimmunoassay of insulin, it has been well known that various substances affect the secretion of insulin from the pancreas (Williams and Ensinck 1966). Although an increase in plasma insulin was observed after the glucagon injection (Yalow et al. 1960), this was attributed to hyperglycemia induced by glucagon until 1965, when Samols et al. demonstrated its direct effect upon insulin secretion in man. Since then, glucagon-induced insulin secretion was confirmed by in vivo (Ketterer et al. 1967) or in vitro experiment (Turner and McIntyre 1966). On the other hand, diabetes mellitus is characterized by absolute or relative deficiency of insulin action. However, there is no definite difference between normal subjects and diabetic patients as far as the fasting level of plasma insulin is concerned (Yalow and Berson 1960). Therefore, glucose loading test has been widely employed in the investigation of plasma insulin levels in diabetic Received
for publication,
March
12, 1975. 103
104
A. Ohneda
et al.
patients. However, it is no always able to discriminate the insulin response to glucose in diabetics from that in the normal subjects (Ohneda et al. 1974). The present study was performed in order insulin response to glucagon in diabetes mellitus
to investigate the difference in the compared with that to glucose and
tolbutamide.
MATERIALS AND METHODS Eight healthy subjects and 10 diabetic patients were studied. In each group, an oral glucose tolerance test (GTT) was followed by an intravenous glucagon test (GT) and a tolbutamide-glucagon test (TGT) at intervals of several days. These were carried out after an overnight fast. In diabetic subjects, these tests were performed prior to the start of the therapy for diabetes mellitus. In GTT, 50 g glucose 30-min intervals for 2 hr.
was administered
by
mouth
and blood
samples
were
drawn
at
In GT, after sampling the base line blood, I mg glucagon dissolved in 2 ml saline, which was donated by Novo Institute, AG., was injected into the cubital vein within 30 sec and blood samples were obtained 1, 3, 6, 10, 15, 20, 30, 45, 60, 90 and 120 min after the glucagon injection. In TGT, after two base line samples were drawn, 1 g tolbutamide in 5% solution (Rastinon,?? Hoechst, A.G.) was injected into the antecubital vein within 2 min and blood samples were drawn 3, 6, 10, 20, 30, 45 and 60 min after the start of the injection. Just after drawing blood sample at 60 min, 1 mg glucagon was rapidly injected intravenously and blood samples were obtained at the same schedule as in GT. Capillary by
the
the
blood
glucose
heparinized
blood
was
stored
at
in
from
(Teller
and
centrifuged
was
the
The
amount
15
ear
poured
assay.
Plasma
lobe
and
Blood
was
the
glass
into after
glucagon
of
the
1956).
immediately
until
(1962).
insulin
obtained
method
syringes
20•Ž
method
was
oxidase
completion
insulin
was
used
glucose from
tubes
the
preparation
blood
obtained
chilled
in
the
test
of measured
in
this
was the
by
study
determined
cubital an and
the
vein
ice
into
box.
The
plasma
was
Morgan-Lazarow
was
proved
to
contain
mU/mg.
The diabetic patients were divided into three groups according to the fasting level of blood glucose, mild (3 cases, less than 120 mg/100 ml), moderate (3 cases, 120 to 200 mg/ 100 ml) and severe diabetics (4 cases, more than 200 mg/100 ml). The mean values and the standard analyses were performed by Student's
errors t test.
of mean
were
calculated
and
the statistical
RESULTS Glucose
tolerance
Blood diabetic rose
glucose
Plasma
the
ml
insulin
7.5•}1.3 ƒÊU/ml returned the
reached
mild,
level
at
30
reached
and
of
normal the
level severe
208.0•}18.5
120
diabetics
at
min
to
normal
reached the
of The
104.0•}1.2,
levels
of the
the
from
peak
blood mild
levels
at
the
fasting at
of
188.0•}33.3 glucose diabetics
after
the
glucose of
level
64.9•}12.6 ƒÊU/ml fasting
and
blood
initial
increased
level
subjects
controls,
and
fell
min.
in
the
normal
ml
glucose
were
peak 60
in
the
subjects
peak
at
The
In
mg/l00 blood
the
GTT
1.
87.4•}1.8
in
initial
during
Fig.
Then
respectively. level
in of
GTT
the
moderate
insulin
min.
and to
mg/100 ml, the
plasma presented
during
of
11.8
are fasting
mg/100
then in
and
patients from
•} 4.1
test
blood
152.4
120
min
60
min
,
glucose
and
214
oral
glucose
, 369.0•}61.1
.
level
.0•}
at
90
Glucagon-Induced
Fig.
1.
Blood
glucose
diabetic
in
severe
diabetics.
the
tolerance
moderate
severe
The
maximal
Glucagon
plasma
of
glucagon
and
plasma
mg
of
peak
in
test
in
moderate
mg/100 glucose
of
and
ml
was
plasma
normal
and
diabetics; •~,
120
min as
in
mild,
7.1*4.0 in
at
observed,
insulin
and
45.3•}10.7 ƒÊU/ml
the
mg/100
the
the
mild in
in
the
,ƒÊU/ml,
8.1•}2.5 ƒÊU/ml
in
at
at
3
all
45
the
min.
In
the
2.
of
the
glucose moderate
respectively.
diabetics,
the
29.5•}
severe
to
rose
diabetics.
glucagon
The
response In
reached in
moderate
diabetics
of
min. 90
60
min.
mild
the
min.
In
but
plasma
the
group
with
reached
the
glucose
each
reached insulin
diabetics,
peak
and
blood
at
after
Thereafter
of
the
the
min
6.6•}1.6 ƒÊU/
injection
the
from
20
level
at
the
9.5•}3.2 ƒÊU/ml
rose
level
3
intravenous
ml
initial
line at
and
insulin
glucose
the
base
groups.
115.3•}4.7
the
mg/100
5.3•}0.4 ƒÊU/ml
after
diabetic
of
Blood
to the
subjects.
of
after
143.9•}2.2
66.1•}9.9 ƒÊU/ml
Plasma level
Fig.
returning
returned
normal
insulin
from
glucose
line
fasting min.
of
and
base
in level
subjects,
level
the
plasma
immediately
blood
in
the
shown peak
gradually
the
ml from
are
normal
peak
decreased
and
the
increased
than
from
glucose
to
diabetics,
later
rose
17.7 ƒÊU/ml
tolerance
diabetics,
3.7•}2.3
was
glucagon
fell
the
blood
the
insulin of
increased
to
levels
diabetics
91.4•}1.2
insulin
glucagon
13.5
in
reached
glucose
fasting
moderate
injection
plasma
the
glucose
392.0*26.9
response
9.3•}4.0,
insulin
the
1
level
group
The were
changes
injection
ml
oral mild
test
The
The
during
and
insulin
decreased.
in
subjects; o,
less
diabetics
10.2 ƒÊU/ml
insulin
diabetics
The
was
and
plasma normal
105
(Mean•}S.E.)
diabetics.
fasting
and
subjects.??,
severe
min
Insulin Secretion in Normal and Diabetic Subjects
level mild
to blood
of
186.0•} diabetes
peak
of
rose
from
49.0•} the
106
A. Ohneda
et al.
Fig. 2. Blood glucose and plasma insulin during intravenous diabetic subjects.
initial 30
level
min
The
of
after
of
still
the
The
base
The
The
peak
increase
The
line in ƒÊ
mean
The level
U/ml
to
min. the at
of
the
min
peak
blood
mg/
of
mg
after level
returned glucagon of
In
base
level
the to
120
group the
min
insulin
line
peak
mg/100
level
4.7+0.7
with
was
was
207.3•}12.1
of
severe
of
120
min. to
the
blood
mg/100 mg/100
in
ml
diabetes,
268.5•}17.7
minimum at
at ,ƒÊU/ml
228.5•}17.0
16.4+3.8 ƒÊU/ml
glucose
and
plasma
a
decrease
caused 100
The
ml
to
the
plasma
the
ml
ml
severe
and
diabetic
6 min.
of
was 76.1•}5.7 to injection
72.0•}4.9 ƒÊU/ml
the
injected
at ml
initial
level
at
the 70
of
60
base
to
peak 105
line
the
ml line
initial
125.8•}2.8
min. level
100
glucose of
Plasma of
shown
in
from
base
blood
the at
mg/ the
fell
min,
are
glucose
58.4:0.2
then
to
TGT
blood
from
6 min,
mg/100
in
in
rose
at
from
insulin
nadir
insulin
69.4+13.1 ƒÊU/ml
glucagon
level and
the
line
206.8•}11.4
was
injection
peak 1
min.
plasma
level
controls.
After
80
of
87.9•}2.7
preinjection
abruptly the
levels
normal
base
at
of
to
the
level
level
and
test
tolbutamide
the
6
of
in
insulin
Tolbutamide-glucagon
3.
line glucose
peak
returning
from at
blood
elevated.
the
injection,
increased
from
min.
group.
reached
39.3+22.5 ƒÊU/ml
rose
45
and
glucagon
insulin
maximum
at
the
plasma
glucose
140.3•}9.9
glucagon test in normal
the at of
Fig. base
30
min
6.3+0.7 evel
increased mg/100 insulin
10.4•}6.6 ƒÊU/ml
at
60
from ml rose to
min.
In the diabetic groups, blood glucose continued to fall gradually after the tolbutamide injection until the time of 60 min and the glucagon injection induced
Glucagon-Induced
Insulin Secretion in Normal and Diabetic Subjects
Fig. 3. Blood glucose and plasma insulin after tolbutamide and diabetic subjects. the
same
mild
increment
diabetics,
nadir
of
rose
76.0
and
the
60-min
80
the 90
severe
The
increment
severe
of
diabetics
of
response the
were
level
rose
of
plasma
after
maximal 28.0•}10.6,
levels
at
either
than
and
the
also
insulin and
in
the
the
28.4•}7.4,ƒÊU/ml,
the The
mg/100
nil
level
the
of
glucagon mg/100
glucagon
was
controls. mild,
The moderate
respectively.
markedly in
from
fasting
or
normal
to
min.
296.5•}47.6
12.0•}2.7 ƒÊU/ml,
was
plasma
27.7•}10.3
of
tolbutamide in
60
After
injection
glucagon of
the
peak
the
glucose
fell
at
174.7•}5.0
min.
the
to
returning
glucose
from
60
the
to
tolbutamide 8.8•}3.4
after
ml
blood
min,
ml
to
fell
In
107.3•}5.5
80
blood
glucose
reached
groups
at
mg/100
glucose
insulin
30.7•}9.1, insulin
blood
controls. of
injection
nil
diabetics,
mg/100 and
glucagon
121.0•}7.4
blood
diabetic
were
The
in
normal level
mg/100
of
increase
the
fasting the
moderate level
followed by glucagon in normal
in
the
142.3•}2.6
the
insulin
that
After
247.0•}29.3
glucose
plasma
of
diabetics,
plasma
as from
min.
the
an
of
all
60
In to
level
diabetics
groups.
min.
severe
in
at level
caused
remarkable
and
nil
peak
the
The
levels
100
150
blood
min.
maximal
diabetic
at
the
glucose decreased
150.7•}3.6
In to
injection
less
mg/
injection
281.0•}34.7
blood
glucose
the
of
min.
at
3.3
level
level
glucagon
ml
f
reached
fasting
at
of
blood
107
mild,
reduced moderate respectively.
in
the and
108
A. Ohneda
et al.
Fig. 4. Comparison of maximal insulin response to various stimuli with that in diabetic subjects.
in normal
subjects
Comparison of the maximal responses to various stimuli in the normal subjects with those in diabetic patients The maximal responses of plasma insulin to various stimuli in the normal subjects and the diabetic patients are presented in Fig. 4. The maximal insulin response to glucose was decreased in all the diabetic groups but a significant dif ference was observed only in the severe diabetic patients in comparison with the normal subjects (p
J. exp.
Med.,
1975,
Glucagon-Induced Diabetic Subjects
116, 103-110
Insulin
Secretion
in Normal
AKIRA OHNEDA, KIYOSHI MATSUDA, MASAMICHI YASUO IIMURA and SHOICHI YAMAGATA
and
CHIBA,
The Third Department of Internal Medicine, Tohoku University School of Medicine, Sendai
OHNEDA, A., MATSUDA, K., CHIBA, M., IIMURA, Y. and YAMAGATA,S. Glucagon-Induced Insulin Secretion in Normal and Diabetic Subjects. Tohoku J. exp. Med., 1975, 116 (2), 103-110 Eight normal subjects and ten diabetic patients were studied to compare the response of plasma insulin to glucagon with that to glucose and tolbutamide. Oral glucose tolerance test, glucagon test and tolbutamide-glucagon test were performed at intervals of several days. In glucose tolerance test, insulin response was reduced in the patients with severe diabetes. Plasma insulin increased and reached the peak 3 min after glucagon injection (glucagon I) in the normal controls, while plasma insulin response was reduced in diabetic patients, especially in the severe diabetics. In the normal controls plasma insulin rose and reached the peak 6 min after the tolbutamide injection and thereafter fell to the initial level. Glucagon injection following tolbutamide (glucagon II) caused the rise in insulin in the control subjects. In diabetics insulin response to either tolbutamide or glucagon 1 was reduced. Tolbutamide or glucagon II caused a significant difference in plasma insulin response in all the diabetic groups compared with the normal subjects, while glucose or glucagon I showed a significant increment of plasma insulin between the normal subjects and the severe diabetics. These results suggest that injection of tolbutamide as well as glucagon II provides a definite discrimination of insulin response in diabetics from the normal controls. The usefulness of the tolbutamide - glucagon test in the diagnosis of diabetes mellitus was discussed. glucose tolerance test; glucagon test; tolbutamide-glucagon test; plasma insulin
Since the development of radioimmunoassay of insulin, it has been well known that various substances affect the secretion of insulin from the pancreas (Williams and Ensinck 1966). Although an increase in plasma insulin was observed after the glucagon injection (Yalow et al. 1960), this was attributed to hyperglycemia induced by glucagon until 1965, when Samols et al. demonstrated its direct effect upon insulin secretion in man. Since then, glucagon-induced insulin secretion was confirmed by in vivo (Ketterer et al. 1967) or in vitro experiment (Turner and McIntyre 1966). On the other hand, diabetes mellitus is characterized by absolute or relative deficiency of insulin action. However, there is no definite difference between normal subjects and diabetic patients as far as the fasting level of plasma insulin is concerned (Yalow and Berson 1960). Therefore, glucose loading test has been widely employed in the investigation of plasma insulin levels in diabetic Received
for publication,
March
12, 1975. 103
104
A. Ohneda
et al.
patients. However, it is no always able to discriminate the insulin response to glucose in diabetics from that in the normal subjects (Ohneda et al. 1974). The present study was performed in order insulin response to glucagon in diabetes mellitus
to investigate the difference in the compared with that to glucose and
tolbutamide.
MATERIALS AND METHODS Eight healthy subjects and 10 diabetic patients were studied. In each group, an oral glucose tolerance test (GTT) was followed by an intravenous glucagon test (GT) and a tolbutamide-glucagon test (TGT) at intervals of several days. These were carried out after an overnight fast. In diabetic subjects, these tests were performed prior to the start of the therapy for diabetes mellitus. In GTT, 50 g glucose 30-min intervals for 2 hr.
was administered
by
mouth
and blood
samples
were
drawn
at
In GT, after sampling the base line blood, I mg glucagon dissolved in 2 ml saline, which was donated by Novo Institute, AG., was injected into the cubital vein within 30 sec and blood samples were obtained 1, 3, 6, 10, 15, 20, 30, 45, 60, 90 and 120 min after the glucagon injection. In TGT, after two base line samples were drawn, 1 g tolbutamide in 5% solution (Rastinon,?? Hoechst, A.G.) was injected into the antecubital vein within 2 min and blood samples were drawn 3, 6, 10, 20, 30, 45 and 60 min after the start of the injection. Just after drawing blood sample at 60 min, 1 mg glucagon was rapidly injected intravenously and blood samples were obtained at the same schedule as in GT. Capillary by
the
the
blood
glucose
heparinized
blood
was
stored
at
in
from
(Teller
and
centrifuged
was
the
The
amount
15
ear
poured
assay.
Plasma
lobe
and
Blood
was
the
glass
into after
glucagon
of
the
1956).
immediately
until
(1962).
insulin
obtained
method
syringes
20•Ž
method
was
oxidase
completion
insulin
was
used
glucose from
tubes
the
preparation
blood
obtained
chilled
in
the
test
of measured
in
this
was the
by
study
determined
cubital an and
the
vein
ice
into
box.
The
plasma
was
Morgan-Lazarow
was
proved
to
contain
mU/mg.
The diabetic patients were divided into three groups according to the fasting level of blood glucose, mild (3 cases, less than 120 mg/100 ml), moderate (3 cases, 120 to 200 mg/ 100 ml) and severe diabetics (4 cases, more than 200 mg/100 ml). The mean values and the standard analyses were performed by Student's
errors t test.
of mean
were
calculated
and
the statistical
RESULTS Glucose
tolerance
Blood diabetic rose
glucose
Plasma
the
ml
insulin
7.5•}1.3 ƒÊU/ml returned the
reached
mild,
level
at
30
reached
and
of
normal the
level severe
208.0•}18.5
120
diabetics
at
min
to
normal
reached the
of The
104.0•}1.2,
levels
of the
the
from
peak
blood mild
levels
at
the
fasting at
of
188.0•}33.3 glucose diabetics
after
the
glucose of
level
64.9•}12.6 ƒÊU/ml fasting
and
blood
initial
increased
level
subjects
controls,
and
fell
min.
in
the
normal
ml
glucose
were
peak 60
in
the
subjects
peak
at
The
In
mg/l00 blood
the
GTT
1.
87.4•}1.8
in
initial
during
Fig.
Then
respectively. level
in of
GTT
the
moderate
insulin
min.
and to
mg/100 ml, the
plasma presented
during
of
11.8
are fasting
mg/100
then in
and
patients from
•} 4.1
test
blood
152.4
120
min
60
min
,
glucose
and
214
oral
glucose
, 369.0•}61.1
.
level
.0•}
at
90
Glucagon-Induced
Fig.
1.
Blood
glucose
diabetic
in
severe
diabetics.
the
tolerance
moderate
severe
The
maximal
Glucagon
plasma
of
glucagon
and
plasma
mg
of
peak
in
test
in
moderate
mg/100 glucose
of
and
ml
was
plasma
normal
and
diabetics; •~,
120
min as
in
mild,
7.1*4.0 in
at
observed,
insulin
and
45.3•}10.7 ƒÊU/ml
the
mg/100
the
the
mild in
in
the
,ƒÊU/ml,
8.1•}2.5 ƒÊU/ml
in
at
at
3
all
45
the
min.
In
the
2.
of
the
glucose moderate
respectively.
diabetics,
the
29.5•}
severe
to
rose
diabetics.
glucagon
The
response In
reached in
moderate
diabetics
of
min. 90
60
min.
mild
the
min.
In
but
plasma
the
group
with
reached
the
glucose
each
reached insulin
diabetics,
peak
and
blood
at
after
Thereafter
of
the
the
min
6.6•}1.6 ƒÊU/
injection
the
from
20
level
at
the
9.5•}3.2 ƒÊU/ml
rose
level
3
intravenous
ml
initial
line at
and
insulin
glucose
the
base
groups.
115.3•}4.7
the
mg/100
5.3•}0.4 ƒÊU/ml
after
diabetic
of
Blood
to the
subjects.
of
after
143.9•}2.2
66.1•}9.9 ƒÊU/ml
Plasma level
Fig.
returning
returned
normal
insulin
from
glucose
line
fasting min.
of
and
base
in level
subjects,
level
the
plasma
immediately
blood
in
the
shown peak
gradually
the
ml from
are
normal
peak
decreased
and
the
increased
than
from
glucose
to
diabetics,
later
rose
17.7 ƒÊU/ml
tolerance
diabetics,
3.7•}2.3
was
glucagon
fell
the
blood
the
insulin of
increased
to
levels
diabetics
91.4•}1.2
insulin
glucagon
13.5
in
reached
glucose
fasting
moderate
injection
plasma
the
glucose
392.0*26.9
response
9.3•}4.0,
insulin
the
1
level
group
The were
changes
injection
ml
oral mild
test
The
The
during
and
insulin
decreased.
in
subjects; o,
less
diabetics
10.2 ƒÊU/ml
insulin
diabetics
The
was
and
plasma normal
105
(Mean•}S.E.)
diabetics.
fasting
and
subjects.??,
severe
min
Insulin Secretion in Normal and Diabetic Subjects
level mild
to blood
of
186.0•} diabetes
peak
of
rose
from
49.0•} the
106
A. Ohneda
et al.
Fig. 2. Blood glucose and plasma insulin during intravenous diabetic subjects.
initial 30
level
min
The
of
after
of
still
the
The
base
The
The
peak
increase
The
line in ƒÊ
mean
The level
U/ml
to
min. the at
of
the
min
peak
blood
mg/
of
mg
after level
returned glucagon of
In
base
level
the to
120
group the
min
insulin
line
peak
mg/100
level
4.7+0.7
with
was
was
207.3•}12.1
of
severe
of
120
min. to
the
blood
mg/100 mg/100
in
ml
diabetes,
268.5•}17.7
minimum at
at ,ƒÊU/ml
228.5•}17.0
16.4+3.8 ƒÊU/ml
glucose
and
plasma
a
decrease
caused 100
The
ml
to
the
plasma
the
ml
ml
severe
and
diabetic
6 min.
of
was 76.1•}5.7 to injection
72.0•}4.9 ƒÊU/ml
the
injected
at ml
initial
level
at
the 70
of
60
base
to
peak 105
line
the
ml line
initial
125.8•}2.8
min. level
100
glucose of
Plasma of
shown
in
from
base
blood
the at
mg/ the
fell
min,
are
glucose
58.4:0.2
then
to
TGT
blood
from
6 min,
mg/100
in
in
rose
at
from
insulin
nadir
insulin
69.4+13.1 ƒÊU/ml
glucagon
level and
the
line
206.8•}11.4
was
injection
peak 1
min.
plasma
level
controls.
After
80
of
87.9•}2.7
preinjection
abruptly the
levels
normal
base
at
of
to
the
level
level
and
test
tolbutamide
the
6
of
in
insulin
Tolbutamide-glucagon
3.
line glucose
peak
returning
from at
blood
elevated.
the
injection,
increased
from
min.
group.
reached
39.3+22.5 ƒÊU/ml
rose
45
and
glucagon
insulin
maximum
at
the
plasma
glucose
140.3•}9.9
glucagon test in normal
the at of
Fig. base
30
min
6.3+0.7 evel
increased mg/100 insulin
10.4•}6.6 ƒÊU/ml
at
60
from ml rose to
min.
In the diabetic groups, blood glucose continued to fall gradually after the tolbutamide injection until the time of 60 min and the glucagon injection induced
Glucagon-Induced
Insulin Secretion in Normal and Diabetic Subjects
Fig. 3. Blood glucose and plasma insulin after tolbutamide and diabetic subjects. the
same
mild
increment
diabetics,
nadir
of
rose
76.0
and
the
60-min
80
the 90
severe
The
increment
severe
of
diabetics
of
response the
were
level
rose
of
plasma
after
maximal 28.0•}10.6,
levels
at
either
than
and
the
also
insulin and
in
the
the
28.4•}7.4,ƒÊU/ml,
the The
mg/100
nil
level
the
of
glucagon mg/100
glucagon
was
controls. mild,
The moderate
respectively.
markedly in
from
fasting
or
normal
to
min.
296.5•}47.6
12.0•}2.7 ƒÊU/ml,
was
plasma
27.7•}10.3
of
tolbutamide in
60
After
injection
glucagon of
the
peak
the
glucose
fell
at
174.7•}5.0
min.
the
to
returning
glucose
from
60
the
to
tolbutamide 8.8•}3.4
after
ml
blood
min,
ml
to
fell
In
107.3•}5.5
80
blood
glucose
reached
groups
at
mg/100
glucose
insulin
30.7•}9.1, insulin
blood
controls. of
injection
nil
diabetics,
mg/100 and
glucagon
121.0•}7.4
blood
diabetic
were
The
in
normal level
mg/100
of
increase
the
fasting the
moderate level
followed by glucagon in normal
in
the
142.3•}2.6
the
insulin
that
After
247.0•}29.3
glucose
plasma
of
diabetics,
plasma
as from
min.
the
an
of
all
60
In to
level
diabetics
groups.
min.
severe
in
at level
caused
remarkable
and
nil
peak
the
The
levels
100
150
blood
min.
maximal
diabetic
at
the
glucose decreased
150.7•}3.6
In to
injection
less
mg/
injection
281.0•}34.7
blood
glucose
the
of
min.
at
3.3
level
level
glucagon
ml
f
reached
fasting
at
of
blood
107
mild,
reduced moderate respectively.
in
the and
108
A. Ohneda
et al.
Fig. 4. Comparison of maximal insulin response to various stimuli with that in diabetic subjects.
in normal
subjects
Comparison of the maximal responses to various stimuli in the normal subjects with those in diabetic patients The maximal responses of plasma insulin to various stimuli in the normal subjects and the diabetic patients are presented in Fig. 4. The maximal insulin response to glucose was decreased in all the diabetic groups but a significant dif ference was observed only in the severe diabetic patients in comparison with the normal subjects (p
