Serial Changes in Glucose
Utilization and Insulin and Growth
Hormone Secretion in Acute
Cerebrovascular Disease
BY T. A. HUFF, M.D.,* H. E. LEBOVITZ, M.D., A. HEYMAN, M.D.,
AND L. DAVIS, B.A.
Abttract:
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Serial Changes
in Glucose
Utilization and
Insulin and
Growth
Hormone
Secretion in
Acute
Cerebrovascular
Disease
• Serial studies were made of glucose utilization and insulin and growth
hormone secretion following intravenous glucose tolerance tests given to 16
patients during recovery from acute cerebrovascular disease. Three groups of
patients were identified based on the pattern of change of glucose utilization
during the first month of convalescence. A small group showed a persistent
defective insulin response to glucose and appeared to have had pre-existing
unrecognized adult-onset diabetes mellitus. The two other groups showed either
an immediate suppression of glucose utilization or delayed development of
glucose intolerance associated with an increase in total insulin secretion. Both
of these responses returned to normal by the end of the fourth week. Growth
hormone secretion correlated with the severity of the stroke. Alterations in
glucose metabolism and insulin secretion seem to occur in most patients
following recovery from stroke and undoubtedly reflect transient hormonal or
metabolic changes related to either acute stress or tissue injury, depending on
the interval after the onset of the vascular episode.
Additional Key Words
hyperglycemia
diabetes mellitus
intracranial hemorrhage
• Hyperglycemia and glucose intolerance
have been recognized as frequent findings in
patients with acute cerebral infarction or
intracranial hemorrhage.1"" In some patients
this abnormal glucose metabolism is due to
diabetes mellitus preceding the stroke and
reflects the common association of these two
illnesses. In other instances, evidence of a preexisting or underlying diabetes mellitus cannot
be found and the hyperglycemia proves to be
only an acute transient disturbance in glucose
regulation.
•Present address: Medical College of Georgia, Department of Medicine, Division of Endocrinology,
Augusta, Georgia.
From the Divisions of Endocrinology and Neurology, Department of Medicine, Duke University
Medical Center, Durham, North Carolina.
Supported by the Duke-VA Center for Cerebrovascular Research, NIH Grant NS 06233 and by Grants
AM 01324 and K3 AM 17954.
Stroke, Vol. 3, September-Ocfober 1972
cerebral infarction
A number of possible mechanisms for this
transient alteration in glucose metabolism can
be proposed. (1) It may be caused by the
autonomic and hormonal changes which result
from the acute stress. (2) It may be due to
temporary unmasking of latent diabetes mellitus. (3) It may be the result of metabolic
changes secondary to injury of body tissue.4
(4) It might be due to an irritative effect on
glucose-regulating centers in the brain stem or
hypothalamus such as has been suggested in a
recent study of impaired glucose tolerance in
patients with intracranial hemorrhage.5
The present study was designed to
determine the frequency, duration, degree and
mechanism of the impaired glucose tolerance
in patients with acute cerebrovascular disease.
It reports the serial changes in glucose
utilization and insulin and growth hormone
secretion following an intravenous glucose
tolerance test given at various times during
543
HUFF, LEBOVITZ, HEYMAN, DAVIS
recovery from this illness. Three patterns of
altered glucose-insulin dynamics seem to
appear during recovery from stroke. One may
represent an autonomic or hormonal response
to acute stress. The second may be a metabolic
response to tissue injury. The third is likely to
be the result of previously unrecognized
diabetes mellitus.
Case Material and Methods
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The case material consisted of 16 patients: 13 had
acute cerebral infarction, one had transient
cerebral ischemia and two had intracranial
hemorrhage. Nine were men and seven were
women. Their ages ranged from 36 to 67 years,
with an average age of 51 years. All but one of
the patients (case 9, with subarachnoid hemorrhage) had sudden onset of monoparesis or
hemiparesis associated with other focal neurological deficits. The patients were graded as mild,
moderate or severe, depending on the degree of
alteration in consciousness following the onset of
the stroke. Six patients were considered to have a
mild stroke with no alteration in consciousness at
any time. One of them had vertebral-basilar
insufficiency with recurrent transient cerebral
ischemic attacks (case 14), another (case 9,
mentioned above) had a relatively benign subarachnoid hemorrhage due to rupture of a
congenital berry aneurysm, and the remaining
four had cerebral infarction. The moderate group
consisted of five patients with cerebral infarction
who had clouding of consciousness or confusion
for 24 to 48 hours after the onset of the stroke.
The remaining five patients (one of whom, case
15, had an intracerebral hemorrhage) were
classified as having a severe stroke with considerable alteration in consciousness and required
intravenous or nasogastric tube feeding. Only one
of the 13 patients with infarction had involvement
of the brain stem (case 6). The remaining 12
patients had clinical evidence of unilateral
infarction of the cerebral hemispheres with
aphasia, visual field defects or tonic conjugate eye
deviation to the appropriate side. The presence of
infarction of the cerebral cortex in these cases was
confirmed by the electroencephalographical, brain
scan or arteriographical examinations.
All patients were admitted into the study
within five days after the onset of the stroke.
Patients were excluded if they were known to
have diabetes mellitus, uremia, or recent myocardial infarction, or if they received corticosteroids
(for cerebral edema), thiazides, or other drugs
known to affect insulin secretion. Four of the
patients with severe strokes had received intravenous fluids for two or three days prior to the first
measurement of glucose tolerance. One of them
544
continued to have intravenous feedings for an
additional two weeks. In these cases, the infusate
was changed to normal saline at least four hours
before glucose tolerance was measured. In all
other patients, oral or tube feedings were withheld
overnight prior to testing.
The intravenous glucose tolerance tests
(IVGTT) were carried out as previously described.0 Fasting samples were taken following
which 25 gm of glucose was rapidly infused in a
two-minute period and samples for glucose,
insulin and growth hormone determinations were
drawn at five-minute intervals for one hour. A
2.5-minute sample was also taken for insulin.
Blood glucose was measured by a glucose
oxidase method.7 The logarithm of individual
glucose values was plotted against time. The slope
of the linear segment of the curve was derived by
regression analysis and the regression coefficient
(b) was multiplied by a constant (—230.3) so as
to express K, the rate of glucose fall in the percent
per minute, which represents an estimate of
glucose utilization. K values below 1.0 were
considered diabetic.0 The normal K value previously reported from this laboratory is 1.65 ± 0.17
(mean±SEM). 8
Plasma immunoreactive insulin (IRI) and
growth hormone (IRGH) were measured by the
double antibody technique of Morgan and
Lazarow," using human insulin and growth
hormone standards (obtained from Dr. Mary
Root, Eli Lilly Company, and Dr. A. E.
Wilhelmi). The area under the insulin response
curve was integrated as described previously10 to
allow comparison of total insulin secretion on
sequential tests. Growth hormone data were
treated the same way. We have previously shown
that on repeat studies, control patients show no
significant variation in K and growth hormone
response, and vary by 6% or less with respect to
total insulin secretion.0
Each of these 16 patients received three or
more intravenous glucose tolerance tests during
the 30-day period following their acute cerebrovascular episode. These tests were carried out
during three successive stages after the onset of
the stroke: Period 1, the first five days after the
onset of acute symptoms; Period 2, which
extended from the sixth to sixteenth day after the
onset of the illness, and Period 3, which extended
from the eighteenth to the thirtieth day after the
stroke.
Results
The serial changes in glucose disposal constants and insulin and growth hormone
secretion following intravenous glucose stimulation for each of the patients in the study are
Strokt, Vol. 3, StpHmber-Octobor 1972
o
CO
tern
Vol.
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VI
_
9
I
©
o-
1
•*
to
Co
Mild
Mild
Severe
Moderate
Severe
Severe
Mild
Mild
Mild
Mild
Severe
Moderate
Moderate
Moderate
Moderate
Severe
Severity
2050
8321
5460
5536
7188
848
1151
851
9588
4576
4557
1020
1.27
0.07
4495
2087
0.66
0.03
1.30
1.33
1.43
1.46
1.17
1.18
1.03
1.01
176
1.04
8595
1764
3126
2166
643
0.68
0.13
0.71
0.67
0.61
1699
3437
1362
in
0.48
0.93
0.64
K
0.677
0.076
1.076
0.718
0.981
0759
0.511
0.437
0.379
0.454
0.872
0.583
0.939
0.084
0.863
0.834
1.12
0.593
0.062
0.603
0.696
0.479
IRI Pdl
IBI Pd 1
0.91
0.06
0.93
1.08
0.85
1.07
0.69
0.53
0.99
0.90
1.15
0.88
0.66
0.08
0.82
0.54
0.61
1.25
0.36
0.84
1.97
0.95
K
III
Total
6609
1420
1906
11585
5566
7290
14055
1941
3036
1875
10993
7846
4951
2511
9958
2116
2779
3533
704
2816
4940
2842
Period 2
1.19
0.15
1.08
1.20
1.29
1.18
0.57
1.07
1.09
1.08
2.42
0.96
0.60
0.16
0.93
0.46
0.42
2.00
0.52
1.78
2.99
1.24
K
4707
985
1821
8818
4417
7488
6496
2640
1609
1056
9395
3328
4491
1906
8289
2307
2876
1957
405
2024
1226
2623
IRI
Period 1
Total
0773
0.092
0.955
0761
0794
1.027
0.462
1.360
0.530
0.563
0.855
0.424
0.98
0.08
0.832
1.09
1.03
0.630
0.199
0719
0.248
0.923
IRI Pd 1
IRI Pd 1
145
27
89
90
164
100
283
201
95
70
294
66
253
80
410
145
205
225
47
289
134
253
- Total IROH
Avg. of all
period*
Cl — Cerebral infarction, SH — subarachnoid hemorrhage, CH — cerebral hemorrhage, TIA — transient ischemic attacks. Meaning of other abbreviations (K, Total IRI, IRGH, etc.) described in text.
Group C
Cl
7
Cl
8
SH
9
Cl
10
Cl
11
Cl
12
Cl
13
TIA
14
CH
15
Cl
16
Mean
± SEM
Group B
4
Cl
Cl
5
Cl
6
Mean
± SEM
Group A
Cl
1
Cl
2
Cl
3
Mean
± SEM
Dlognotls
Period 1
Total
K Values, Insulin Secretion and Growth Hormone Secretion Following 25 Gm Intravenous Glucose During Periods 1, 2, and 3 after Acufe Cerebrovascular
Disease
TABLE 1
5
N
H
c
o
1n
o
i/i
—
Z
m
n
z
>
a
SERIAI
HUFF, LEBOVITZ, HEYMAN, DAVIS
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given in table 1. The K value is the glucose
disposal constant as denned in the section on
Case Material and Methods. Total IRI is the
area under the plasma insulin curve for 60
minutes following the glucose stimulation.
Previous studies with intravenous glucose
tolerance tests in normal patients have shown
marked individual variation in both K values
and total IRI secretion within the normal
population, so that it is not feasible to
determine the significance of changes in these
parameters by comparing the differences of the
mean values where small populations are
involved.0'8 Since these parameters are relatively constant in the same patient, a more
valid analysis may be obtained in a study such
as the present one, by using each patient as his
own control and analyzing the data by paired
differences. Since no data on our patients are
available from the pre-stroke period, we have
arbitrarily set K values and total IRI in Period
2 as the reference. The total IRI in Period 2
was given an arbitrary value of 1.0 and the
total IRI's in Periods 1 and 3 were compared
to it. These data are given in table 1 as:
IRI PERIOD 1
IRI PERIOD 2
IRI PERIOD 3
IRI PERIOD 2
The pattern of insulin secretion in response to
glucose was further analyzed by comparing the
initial discharge of insulin (that released in the
first 20 minutes after glucose administration)
to the total insulin secretion (that released
during the entire 60 minutes after glucose
TABLE 2
Ratio of Initial IRI to Total IRI in Control Subjects and Stroke Cases During Repeated Studies
Stroke
cau
Group A
Group B
Group C
1
2
3
Mean
* SEM
4
5
6
Mean
=fa SEM
7
8
9
10
11
12
13
14
15
16
Mean
± SEM
Control
subjects*
1
2
3
4
5
Mean
± SEM
Period 1
Period 1
Period 1
.438
.537
.532
.502
.032
.359
.304
.380
.348
.023
.427
.552
.293
.518
.361
.410
.377
.418
.558
.654
.457
.035
.313
.447
.659
.473
.100
.364
.253
.387
.335
.041
.397
.523
.329
.486
.390
.405
.354
.413
.497
.535
.433
.023
.578
794
.621
.664
.066
.347
.274
.371
.331
.029
.490
.515
.333
.438
.307
.498
.456
.445
.708
.600
.479
.037
.477
.583
.633
.483
.547
.554
.030
.452
.546
.619
.524
.663
.561
.037
Period
compared
P vofcioi
1 versus 2
2 versus 3
1 versus 3
<0.05
1 versus 2
2 versus 3
1 versus 2
NS
NS
NS
1 versus 2
2 versus 3
1 versus 3
NS
NS
NS
1 versus 3
NS
NS
NS
•Data from reference 6.
546
Sfrole, Vol. 3, Sopfember-Ocfobar 1972
SERIAL CHANGES IN GLUCOSE UTILIZATION
administration). These values, designated as
Initial IRI , are shown in table 2.
Total IRI
GLUCOSE DISPOSAL CONSTANT
30
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Total growth hormone secretion for each
of the patients was calculated for each of the
three studies and then averaged for each
patient. These measurements are tabulated as
total IRGH and represent an average of all
three study periods.
Based on the pattern of change of the K
value, three groups of patients were identified.
Patients in Groups A and B had abnormally
low K values in Period 1. These later became
normal in Group A, but remained abnormal in
Group B. Group C was characterized by
normal K values in Periods 1 and 3, but the K
was depressed in Period 2. Figure 1 illustrates
these data.
Group A consisted of three patients in
whom the K value was initially low (mean
0.68) but improved in Periods 2 and 3. The
insulin secretion in response to glucose was
maximal in Period 2 and was 59% and 6 3 % of
maximum in Periods 1 and 3, respectively. As
shown in table 2, the decreased insulin
response to glucose in Period 1 was associated
with a reduction in the initial discharge of
insulin, which accounts for half the total
insulin response, instead of two-thirds of the
total seen in Period 3 (50.2% versus 66.4%,
GTOUPA (3pU)
Illstdoy)
GROUP C (lOptsI
20
I R I RELATIVE TO PERIOD D
lil
n
100
75
50
25
POST-STSOKET
fERKJC
n
'
m
i
n
m
FIGURE 1
The solid bars indicate mean glucose disposal constant
(K values) following intravenous glucose in groups of
patients during the three study periods after acute
stroke. Stippled bars indicate mean plasma immunoreactive insulin responses relative to Period 2 determined at these times. Brackets indicate ± 1 S.E.M.
p < 0.05). Period 2 would seem to be
associated with insulin resistance, since total
insulin secretion is maximal, but glucose
utilization is still impaired in comparison to
Period 3. Figure 2 illustrates the serial changes
in glucose utilization, and plasma insulin and
growth hormone responses to glucose in a
INTRAVENOUS GLUCOSE TOLERANCE TESTl25gm
Post-Stroke
Period
GROUP 8 (Jpts)
II(7thday)
SB47 r rNM BSU&
S t . I l l Slrokl
III 120th. doy)
K=0.95
20
40
60
Time (Minutes)
FIGURE 2
Serial changes in glucose utilization (K value), plasma insulin and growth hormone responses
to intravenous glucose in a representative patient of Group A (patient No. 3).
Stroke, Vol. 3, September-October 1972
547
HUFF, LEBOVITZ, HEYMAN, DAVIS
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representative Group A patient.
Group B consisted of three patients in
whom the K value remained abnormally low in
all three of the study periods. There was no
sharp initial discharge of insulin after glucose
injection (table 2) and the pattern of insulin
secretion during the hour was consistent with
that noted in adult-onset diabetic patients. The
total insulin secretion during each of the three
periods did not differ significantly. The findings
in a representative Group B patient are shown
in figure 3. These three patients appear to have
had pre-existing unrecognized diabetes mellitus, and it is of note that they showed no
alteration in glucose utilization or insulin
secretion during the evolution of the stroke.
Group C comprised ten patients, the
largest number in our study. The initial K
values for these patients were all within the
normal or borderline range (greater than 1.0)
but fell in Period 2, and rose toward their
initial value in Period 3. As noted in table 1
and figure 1, insulin secretion was maximal in
Period 2, was 68% of maximum in Period 1,
and 77.3% in Period 3. Thus Group C patients
showed a striking degree of insulin resistance
in Period 2 but, unlike the Group A patients,
did not show alteration in initial insulin
secretion (table 2) in Period 1 or 3 (0.457
versus 0.479, respectively). Figure 4 demon-
strates the changes in a representative patient
in Group C.
The three groups of stroke patients were
separable not only by their K patterns, but also
on the basis of significant differences in the
degree of acute insulin response to glucose
during Period 3. This is shown in table 2 by
Initial (0 to 20 minutes) IRI/Total (0 to 60
minutes)/IRI ratios of 0.66, 0.33, and 0.48
for Groups A, B, and C (table 2). In a group
of normal subjects, the initial discharge of
insulin accounts for over half the total
secretory response to rapid intravenous glucose
loading as shown by a ratio of initial IRI/Total
IRI of 0.545 ± 0.030 with no change in serial
studies (table 2). In the Group A patients, this
ratio was significantly lower in Period 1 than in
Period 3 (0.50 and 0.66, respectively),
reflecting impaired initial insulin secretion, and
correlated with the abnormal K. Some evidence
is available to suggest that glucose utilization
(K) is primarily influenced by the initial
insulin discharge. In contrast to the Group A
patients, no changes in the Initial IRI/Total
IRI ratio between Periods 1 and 3 were
encountered in Groups B and C. In Group B,
the ratio of 0.33 reflects marked impairment of
acute insulin release, which has previously
been shown to be characteristic of the adultonset diabetic state.
INTRAVENOUS GLUCOSE TOLERANCE TEST (25gmjLMc«nNFFBS-223m,v.
Hudlroll Stroll
Post-Stroke
Period
IlHISth day)
I (3rd day)
K=046
J(=067
22
20
20
40
60 0
20
40
Time (Minutes)
60
0
20
40
60
FIGURE 3
Serial changes in glucose utilization (K value), plasma insulin and growth hormone responses
to intravenous glucose in a representative patient of Group B (patient No. 5).
548
$trok;
Vol. 3, Septtmber-October 1972
SERIAL CHANGES IN GLUCOSE UTILIZATION
INTRAVENOUS GLUCOSE TOLERANCE TEST (25gm ) GE ie»r NU FBS-IK*,-*
Mooirotl Strokl
I (7th day)
TJII2l5tdoy)
24|
O
2 2E
o
m
20S1
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0 *=
5 o
0
20
40
60
Time (Minutes]
20
40
60
I
FIGURE 4
Serial changes in glucose utilization (K value), plasma insulin and growth hormone responses
to intravenous glucose in a representative patient of Group C (Patient No. 16).
No relationship was noted between
changes in K value and insulin secretion and
the severity of the cerebrovascular episode.
Approximately equal numbers of patients with
severe and moderate strokes occurred in
Groups A, B, and C. However, all patients
with mild strokes fell into Group C.
The pattern of growth hormone secretion
was quite variable. Resting growth hormone
levels were not elevated, but in a sizable
number of studies in Period 1 there was a rise
in plasma growth hormone following the administration of the glucose. In most patients this
rise in growth hormone secretion after glucose
tended to decrease after Period 1 but exceptions were frequent, particularly in the moderately and severely affected patients. In four of
the cases, total growth hormone secretion
exceeded 200 ng-min/ml in Period 3. Groups
A, B, and C did not differ significantly with
respect to growth hormone secretion (table 1,
last column).
However, there was a definite correlation
of growth hormone secretion with the degree of
severity of the stroke. An average total growth
hormone secretion for each patient was
obtained by averaging the response in each of
the three test periods. Although the changes
were modest (a total growth hormone secretion
of 200 ng-min/ml represents an average
Stroke, Vol. 3, September-October 1972
plasma level of 3.7 ng/ml) the mean growth
hormone secretion varied directly with the
severity of the cerebrovascular episode (fig.
5).
Discussion
Serial intravenous glucose tolerance tests
carried out in the first four weeks following
acute stroke revealed three patterns of altered
glucose-insulin dynamics. Three of the 16
patients (Group B) showed a persistent
•S 2 0 0 -
100 -
Moderate
ISpts)
Mild
fepls)
FIGURE 5
Mean growth hormone secretion in relation to severity
of the cerebrovascular episode. Brackets indicate
±1 S.EM.
549
HUFF, LEBOVITZ, HEYMAN, DAVIS
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defective pancreatic response to glucose characteristic of diabetes mellitus. These three
patients probably had previously unrecognized
adult-onset diabetes mellitus. In the remaining
13 patients the alterations in glucose-insulin
responses were transient and consisted of either
an immediate suppression of glucose utilization
(Group A—three patients) or delayed development of glucose intolerance associated with
an increase in total insulin secretion (Group
C—ten patients). Both of these responses
returned to normal by the end of the fourth
week and undoubtedly reflect transient metabolic and hormonal changes related to the acute
cerebrovascular episode. The exact mechanism
for these disturbances in glucose regulation is
not understood, but several explanations seem
possible.
One mechanism for the impairment of
glucose utilization which occurred during
Period 1 in Group A patients might be the
release of catecholamines due to an autonomic
response to acute stress. Catecholamines can
elevate blood glucose through its effects in
increasing hepatic release of glucose and
blocking peripheral uptake of glucose. In
addition, infusion of pharmacological quantities of epinephrine is known to inhibit insulin
release in man.10 Porte and Bagdade 11 have
suggested that there are at least two separate
pools of insulin within the pancreatic beta cell:
a storage pool which is released immediately
upon glucose challenge and a second pool
which depends on intact insulin synthetic
mechanisms and accounts for continued insulin
secretion on exposure to prolonged hyperglycemia. Because the first pool is specifically
suppressed by epinephrine, the initial insulin
release should be most markedly affected if
catecholamines were inhibiting insulin release.
In the Group A patients, during the later stages
of convalescence (Period 3), the initial insulin
release (first pool) accounted for 66% of the
total insulin response to glucose. Immediately
after the stroke, however, the initial discharge
was significantly less, 5 0 % , as one might
expect to find if catecholamine secretion were
increased at that time. There is some suggestion that increased catecholamine secretion
after nonspecific stresses (e.g., surgical operation, severe burns and myocardial infarction
with shock) may impair insulin release and
result in hyperglycemia. Tomomatsu and his
550
co-workers12 have reported sudden elevations
of catecholamine secretion in patients with
intracranial hemorrhage, but only a minimal
increase in patients with cerebral infarction.
Other workers, however, could demonstrate
only occasional acute elevation of urinary
catecholamine in patients with intracranial
hemorrhage.13 All of the Group A patients had
cerebral infarction and thus are unlikely to
have had significant increases in urinary
catecholamine secretion. However, we cannot
dismiss the possibility that these patients were
unusually sensitive to small increases in the
circulating catecholamines.
An acute autonomic response to stress
could not account for the transient resistance
to endogenous insulin observed in Group C
patients. These patients developed glucose
intolerance two weeks after the onset of stroke,
at which time there would be no increase in
catecholamine secretion. On the other hand, an
alteration in pituitary-adrenal function, such as
that observed by Jenkins et al.,14 in patients
with subarachnoid hemorrhage might contribute to the insulin resistance in our Group C
patients. These workers observed disturbances
in the diurnal rhythm of plasma cortisol and
abnormal responses to metapyrone and dexamethasone for as long as four weeks after
bleeding from an aneurysm of the circle of
Willis. No adequate data are available as to the
pattern of pituitary-adrenocortical regulation
following cerebral thrombosis.
A more likely explanation for our results
is the possibility that the insulin resistance and
abnormal glucose utilization observed in
Groups A and C are related to an hypercatabolic response to injury. In patients, as well as
experimental animals with fractures, burns or
surgical procedures, marked negative nitrogen
balance, mild hyperglycemia and insulin resistance are often found.16 There are also reports
of decreased glucose utilization and increased
insulin response to intravenous glucose in the
second week after acute myocardial infarction,6 a pattern similar to that observed in our
Group C patients. In patients with severe
burns, laboratory evidence of diabetes mellitus
and negative nitrogen balance which is reversible only with large doses of insulin have been
found to persist for two to three weeks.16
Although there are no published data on total
Stroke, Vol. 3, S»pfemb«r-Ocfober 7972
SERIAL CHANGES IN GLUCOSE UTILIZATION
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urinary nitrogen excretion after stroke, preliminary data indicate that negative nitrogen
balance occurs during convalescence of stroke
in the absence of complicating infections.17
There is also evidence that experimental
hemispherectomy in monkeys produces prolonged negative nitrogen balance.38 The combination of glucose intolerance, insulin resistance
and nitrogen loss in patients and animals with
brain damage would indicate that acute
cerebrovascular disease, such as was seen in
our patients, might result in a metabolic
response similar to that seen with other tissue
injuries.
There have been two recent reports
describing impaired glucose tolerance after
stroke, but neither of them are entirely
comparable to the present study. In the study
by Hallpike et al.,B all of the patients had
subarachnoid hemorrhage. The abnormal oral
glucose tolerance and mild hyperinsulinemic
response observed in his patients during the
first week after their hemorrhage usually
disappeared when the tests were repeated two
to three months later. The patients studied by
Kawiak and Stelmasiak4 showed impaired
intravenous glucose tolerance and insulin
resistance within three days after acute cerebral
hemorrhage or infarction, but the studies were
not repeated later in convalescence. It is of
interest that neither of the above studies
measured glucose responses during the period
of convalescence in which we found the most
significant changes.
Although a number of animal studies
have shown that injury to specific areas of the
brain, such as the floor of the fourth ventricle,
results in abnormal glucose regulation, there
was no evidence in the present study to
indicate that disruption of specific brain centers
was necessary for alteration in glucose response. The type and location of the brain
lesion in our cases varied considerably but
seemed to have little effect on the pattern of
glucose intolerance. There was likewise no
definite relationship between the severity of the
stroke as determined by the alteration in
consciousness and the changes in glucose
metabolism. However, there was a correlation
between the alteration in growth hormone
secretion and the severity of the stroke.
Although there was a small increase in
secretion of this hormone observed in our
Stroke, Vol. 3, Sepfember-Ocfober 7972
patients with severe stroke, it is unlikely that
this was a factor in the development of glucose
intolerance and insulin resistance in most of
our patients because of the small magnitude of
the change in those with mild or moderate
strokes.
Acknowledgment
The authors are pleased to acknowledge the expert
technical assistance of Miss Sylvia White.
References
1. Walton J N : Subarachnoid Hemorrhage. E & S
Livingstone, Ltd., Edinburgh, 1956
2. Heyman A, Fields WS, Keating RD: Joint
study of extracranlal arterial occlusion. V I .
Racial differences in hospitalized ischemlc
stroke patients. JAMA, in press
3. Heyman A, Nefzger MD, Acheson R: Mortality
of stroke among U. S. veterans In Georgia and
five western states. IV. Clinical observations. J
Chron Dis, to be published
4.
Kawiak W, Stelmasiak Z : Investigations on
glucose metabolism in patients with cerebrovascular accidents. I. Intravenous test on
glucose tolerance In patients after cerebral
stroke. Polish Med J 6: 942-949, 1967
5. Hallpike JR, Claveria LW, Cohen NM, et a l :
Glucose tolerance and plasma insulin levels in
subarachnoid haemorrhage. Brain 94: 1 5 1 164, 1971
6. Lebovitz HE, Shultz KT, Matthews ME, et al:
Acute metabolic responses to myocardial infarction. Circulation 39: 171-181, 1969
7. Saifer A, Gerstenfeld S: Photometric microdetermination of blood glucose with glucose
oxidase. J Lab Clin Med 51 : 448-460, 1958
8. Horton ES, Johnson C, Lebovitz HE: Carbohydrate metabolism in uremia. Ann Int Med
68: 63-74, 1968
9. Morgan CR, Lazarow A : Immunoassay of
insulin: Two antibody system. Plasma insulin
levels of normal, subdiabetic and diabetic rats.
Diabetes 12: 11 5-126, 1963
10. Huff TA, Lebovitz HE: Dynamics of insulin
secretion in myotonic dystrophy. J Clin Endocr
2 8 : 9 9 2 - 9 9 8 , 1968
11. Porte D Jr, Bagdade JD: Human Insulin
secretion: An integrated approach. Ann Rev
Med 2 1 : 219-240, 1970
12. Tomomatsu T, et a l : ECG observations and
urinary excretion of catecholamines In cerebrovascular accidents. Jap Circ J 28: 905-912,
1964. Cited In Excerpta Medica Section 8: 18:
1218, 1965
551
HUFF, LEBOVITZ, HEYMAN, DAVIS
13. Kawiak W, Stelmasiak Z : Urinary excretion of
3-methoxy-4-hydroxy-mandelic acid (VMA) in
patients after cerebral stroke. Neurol Neurochir Pol 1 : 301-307, 1967. Cited in Excerpta
Medico Section 8A: 2 1 : 144, 1968
14. Jenkins JS, Bucknell M, Carter AB, et a l :
Hypothalamic-pituitary adrenal function after
subarachnoid haemorrhage. Brit Med J 4 :
707-709, 1969
15. Kinney JM, Long CL, Duke JH: Carbohydrate
and nitrogen metabolism after injury. In
Porter R, Knight J (eds) : Energy Metabolism in
Trauma. J & A Churchill, London, p 103, 1970
16. Hinton P, Allison SP, Littlejohn S, et a l :
Insulin and glucose to reduce catabolic response to injury in burned patients. Lancet I:
767-769, 1971
1 7. Huff TA: Unpublished data
18. Wolfman EF, Coon WW, Schwartz S: Sodium
retention following experimental lesions of the
precommissural septum in the monkey. J Surg
Res 6: 2-18, 1966
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552
Stroke, Vol. 3, S»ptemb»r-Odob»r
1972
Serial Changes in Glucose Utilization and Insulin and Growth Hormone
Secretion in Acute Cerebrovascular Disease
T. A. Huff, H. E. Lebovitz, A. HEYMAN and L. Davis
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Stroke. 1972;3:543-552
doi: 10.1161/01.STR.3.5.543
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