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The association of amyotrophic lateral sclerosis (motor neuron disease) and carbohydrate intolerance, a clinical study
The Association of Amyotrophic Lateral Sclerosis (Motor Neuron Disease) and Carbohydrate Intolerance, A Clinical Study RICHARDTXER
B~JURGENSTEINKEANDH. Eleven of 13 consecutive patients with amyotrophic lateral sclerosis (ALS) exhibited an abnormality in glucose utilization, detectable by oral and intra-
abnormality persisted despite forced high carbohydrate intake and was present in patients with either severe or mild form of ALS. The explanation of
venous glucose tolerance tests and blood glucose
response
to tolbutamide.
this abnormality is not apparent.
This
MYOTROPHIC LATERAL SCLEROSIS (motor neuron disease) is a disease affecting motor neurons which is characterized by a subacute course ending in death. Recently a high incidence of abnormal glucose tolerance has been reportedly2 in these patients. It is the purpose of this study to document the existence of such a metabolic defect, and to clarify its tiature. Data will be presented on 11 consecutive patients with the clinical diagnosis and typical course of amytrophic lateral sclerosis. Carbohydrate metabolism has been assessed by oral and intravenous glucose tolerance, response to tolbutamide, sensitivity to exogenous insulin arid measurement of serum insulinlike activity. The results indicate a high incidence of chemical diabetes, apparently of pancreatic origin.
A
MATERIAL AND METHODS The clinical diagnosis of (motor neuron disease) amyotrophic lateral sclerosis was based on a history of a progressive neurologic deficit involving pyramidal tracts, motor nuclei, or anterior horn cells of the spinal cord. This was corroborated by objective findings of widespread involvement with spasticity, increased reflexes, muscle fasciculations, wasting and weakness.
In some patients
involvement ability.
there was primarily
of the spinal cord. All patients
bulbar
followed
involvement
the typical
and in others
The study took place over a 2 year period with 11 consecutive
tional patients
were not included
as they were long-standing
primarily
course with increasing
diabetics
patients. on therapy
dis-
Two addiin whom
neurologic symptoms and signs of amyotrophic lateral sclerosis developed. The patients were studied as inpatients at the Clinical Research Center of the Peter Bent Brigham Hospital. All patients bohydrate, the patients
received
supervised
a 3 day preparatory
by a dietitian.
were fed by gastric
tube.
diet consisting
If the oral intake The
following
of at least 250 Gm. of car-
was poor due to bulbar tests were performed
after
symptoms, an over-
From the Departments of Medicine and Neurology, Harvard Medical School and the Peter Bent Brigham Hospital and the Baker Clinic Research Laboratory, New England Deaconess Hospital, Boston, Massachusetts. These clinical studies were carried out in the Clinical Research Center of the Harumd Medical School and Peter Bent Brigham Hospital, supported by Grant 8MOl-FR-31-04 fl the National institutes of Health of the Department of Health, Education and Welfare; Public Health Gratis # FR-O.5185-01; T! AM 5077 New York. Received for publication Apr. 22, 1964.
and the Adler
Foundation
Inc.,
Rye,
1376 METABOLISM, VOL. 13, No. 11 (NOVEMBER), 1964
AMYOTROPHIC
night fast,
LATERAL
1377
SCLEROSIS
1 per day, in the following
order:
(1) oral glucose tolerance
test:
100 Gm. of
glucose were given orally and blood samples for glucose were collected fasting, at % hour, 1 hour, 2 hours and 3 hours. The blood glucose was determined by the autoanalyzer on venous blood. To be diagnostic for diabetes two or more of the following blood glucose levels had to be exceeded9 2 hours test; cent were Tho
fasting,
120 mg. and at 3 hours
100 mg. per cent,
a peak or at 1 hour of 160 mg., at
100 mg. per 100 ml.
(2)
Intravenous
glucose
tolerance
glucose in a dose of 0.5 Cm. per Kg. of actual body weight was injected as a 25 per solution within 3-5 minutes and venous blood samples for determination of glucose obtained fasting and starting from midpoint of infusion every 10 minutes for 1 hour. slope of the glucose disappearance was calculated according to Canard* and the value
K considered
to be abnormal
tivity was determined
if less than 1 per cent per minute.
after an overnight
sue assay where oxidation
of glucose
fast. The technic
labeled
in the C-l
(3)
employed position
Serum
insulin-like
ac-
was the rat adipose tisto Cr*Oa
is the index of
activity.6 All sera were assayed at a concentration of 2.5 per cent by dilution with buffer and reported as such in ,,LU per ml. (4) Intravenous tolbutamide response test; 1.0 Gm. of sodium tolbutamide
(Orinase@
period and samples
for blood glucose
sion every 10 minutes
Diagnostic)
was administered
obtained
fasting
for 1 hour. The blood glucose
intravenously
and starting
response
over a 3 minute
from midpoint
was considered
of infu-
to be abnor-
mal when the fall in blood glucose at 20 minutes was less than 25 per cent of the pretest (fasting) value and in addition at 30 minutes was less than 30 mg. per cent.6 (5) Sensitivity to exogenous
insulin;
crystalline
and samples for blood glucose preliminary
results
indicated
insulin,
glucagon-free
were collected
fasting
a great sensitivity
was injected
and every
to exogenous
rapidly
10 minutes
insulin
intravenously for 1 hour. AS
in the customary
dose
of 0.1 units of insulin per Kg. of body weight the dose was reduced to 0.05 units. At this dose the decrease in blood glucose was arbitrarily considered to be normal when a 25-50 per cent fall occurred
within 20-40
minutes
following
was in excess of 50 per cent and to be decreased
injection,
to be exaggerated
if the fall
if less than 25 per cent.
RESULTS
Of 13 consecutive patients with the clinical diagnosis of amyotrophic lateral sclerosis, 2 patients were excluded as they were known diabetics of many years duration. The remaining 11 patients denied symptoms of diabetes mellitus and there was no glycosuria on routine testing. As the oral glucose tolerance test is the accepted method of assessing glucose utilization and as interpretation varies, data available are presented in detail in table 1. By the outlined criteria for diagnosis of diabetes mellitus only 2 patients exhibited a normal curve, 1 a borderline diabetic curve and 7 showed typical diabetic values. Physical inactivity may deteriorate glucose tolerance,7J therefore it is noted if the patient, prior to admission, was ambulatory or confined to bed. Of the 7 patients who demonstrated glucose intolerance, 4 were ambulatory. Table 2 indicates the individual values of K for the intravenous glucose tolerance tests, the per cent fall of blood glucose within 20 minutes of injection of tolbutamide and the maximum per cent fall in blood glucose 20-40 minutes following administration of insulin, as well as the levels of serum insulin-like activity after an overnight fast. Table 3 summarizes the interpretation of each of the tests performed. Two patients, diabetic by oral glucose tolerance were judged nondiabetic by intravenous glucose tolerance test, and by response to tolbutamide. Both had signs of bulbar involvement and both had been fed by gastric tube. The remaining patients showed no discrepancy between oral and intravenous glucose tolerance. The tolbutamide response test followed
1378
STEXNKE
Table l.-Redb
AND
TYLER
of Oral Glucose Tolerance Tests in 10 Consecutive Patients with the Clinical Diagnosis of Amuotrophic Lateral Sclerosis
Patient
Age
C0Ulmellts
F
F. W.
56
Sex F
Bedridden
92
V.H.
31
F
Ambulatory
E. G.
c3
M
Bedridden
M. H.
55
F
Ambulatory.
*/ hr.
1 hr.
2 hr.
3 hr.
Interpretation
202
167
129
Diabetes
108
196 -
173
150
82
Diabetes
92
142
154
136
114
Diabetes
10 !i
2Od
163
122
71
Diabetes
114
210
218
164
47
Diabetes
7,;
236
294
124
64
Diabetes
M2
174
178
154
146
Diabetes
PlYSenCe of Severe Bulbsr symptoms
tube fed J.A.
61
M
Ambulatory
H. V.
56
F
Ambulatory, tube fed
LO.
49
F
Bedridden, tube fed
W. I’.
46
M
Ambulatory
102
164
165
118
104
Borderline
Slight
A.C.
48
M
Ambulatory
94
130
100
100
90
Nondiabetic
Minimal
I.A.
45
F
Ambu!atoru
P4
124
134
114
76
Nondiabetic
Minimal
Table 2.-Composite
Data on 11 Consecutive Patients with the Clinical Diagnosis of Amyotrophic Lateral Sclerosis -____-. ___-
_
IV Glucose
Patients F. W.
V. H. E. G.
_____
Tolerance Value K ___ 0.7
0.9 0.9
L. 0.
0.9 0.9 1.4 1.6
w. P.
0.9
A. C.
I. A.
1.3 1.5
E. B.
0.9
;A? H. V.
IV Tolhutamide
% Fall in Blood Glucoseat 20 min.
IV Insulin, Maximum Serum Insulin-like Activity in y0 Fall in Blood Glucose pU./ml. at 26% between 20 and 40 min.
11 18
66
40
-
13 23 14
66 69
75 -
26 27 25 26 25 23
22 41 35 66 .54 51 58 ..~~.___
100 130 so 120 55 65 6S 165 __. __-
_
closely the intravenous glucose tolerance. The values for serum insulin-like activity uncorrected for dilution exhibited a wide scatter ranging from 40 to 165 PU per ml., mean and standard error being 87 -t 13, respectively. Eensitivity to exogenous insulin in the administered small dose of 0.05 units per Kg. of body weight was cansidered normal in 2 patients, exaggerated in 7 and decreased in 1 patient. There was no relationship between insulin sensitivity, glucose tolerance and levels of circulating insulin-like activity. DISCUSSION
Since Bernard9 reported that a lesion in the floor of the fourth ventricIe can produce temporary glycosuria (piqure diabetique) there has been interest in the relationship between the central nervous system and carbohydrate metabolism. Although much experimental evidence has supported such an interrelationship,lO~ll lesions of the central nervous system rarely are responsible for the appearance of permanent diabetes in patients.12 On the other hand, diabetes has been reported to coexist with a variety of neurolagic disorders as well as with non-neurologic diseases. This is an expected observation as
AMYOTROPHIC
LATERAL
1379
SCLEROSIS
Table 3.-Comparative
Results and Znterpretation of Tests Performed Evaluation of Carbohydrate Metubolkm
Patients
F. W. V. H. E. G. M. H. J. A. H. V. L. 0. w. P. A. C. 1. A. E. B.
Oral
--___-_
GTT
Diabetes Diabetes Diabetes Diabetes Diabetes Diabetes Diabetes Borderline Nondiabetic Nondiabetic -
-___
IV GTT
Diabetes Diabetes Diabetes Diabetes Diabetes Nondiabetic Nondiabetic Diabetic Nondiabetic Nondiabetic Diabetic
IV Tolbutamide
Diabetes Diabetes Diabetes Diabetes Diabetes Nondiabetic Nondiabetic Nondiabetic Nondiabetic Nondiabetic Diabetic
fur
IV Insulin Sensitivity
Exaggerated
Exaggerated Exaggerated Decreased Normal Normal Exaggerated Exaggerated Exaggerated Exaggerated
diabetes mellitus is a common disease with an incidence of at least 2-3 per cent of the total population. la Furthermore, if the disease leads to physical in’activity this per se may deteriorate glucose tolerance. This often results in a state of chemical diabetes characterized by abnormal glucose tolerance but without symptoms of diabetes and not requiring treatment. In such instances, if return to physical activity is possible, glucose tolerance will also return to normal.7*8 In some patients, lack of a preparatory diet may be responsible for temporary glucose intolerance, known as starvation’ diabetes. Furthermore, age seems to influence glucose tolerance. I4 Therefore, it is of utmost importance that patients prior to any glucose tolerance testing are prepared by a high carbohydrate diet, that their age is stated and that the amount of physical activity is assessed. Failure to appreciate this may possibly be the cause for the extraordinarily elevated incidence of chemical diabetes detected in almost any chronic disease. For example, of 222 patients afflicted with arthritis, 57 per cent were found to have an abnormal glucose tolerance,15 similarly of 950 patients with cancer 37 per cent had abn.ormal values,lB of 767 neuropsychiatric ward patients 30 per cent showed a diabetic glucose tolerance.l? AskUpmack l8 found only 2 patients with diabetes in a small series with amyotrophic lateral sclerosis but it is obvi.ous that he discussed overt rather than chemical diabetes. Oti the other hand, CummingP commented that glucose tolerance was normal in 16 patients examined, however, he did not define normal nor present detailed data. In our series of 13 patients with amyotrophic lateral sclerosis, 2 had pre-existent overt clinical diabetes, requiring therapy.. There were 8 additional patients with chemical glucose intolerance as judged by inadequate response to glucose and tolbutamide although they lacked diabetic symptoms. Only 2 patients were unequivocally normal in this regard. All patients exhibited a gradual fall in blood glucose following glucose loading, however, the response of the abnormal group was typically delayed. Fasting values of serum insulin-like activity showed a wide scatter and statistically were not different from 30 normal control values, reported elsewhere.20 The itisulin sensitivity tests indicate that almost all patients with amyotrophic
1380
STEINKE AND TYLER
lateral sclerosis had an exaggerated response to exogenous insulin as the test dose was only half of the customary amount given. Therefore, an abnormal glucose tolerance test in these patients is unlikely to be due to a partial block of glucose uptake by the diseased muscle. Difficult to assess is the importance of bulbar involvement or immobilization in these patients. It remains conjecturable whether or not the bulbar lesion may be directly responsible for the abnormal glucose tolerance (piqure diabetique). There was some degree of correlation between bulbar signs and the presence or absence of the defect but the small number of patients make any conclusion hazardous. Many of the involved patients had normal activity and we believed it unlikely that physical inactivity in itself could account for our findings. If the patients confined to bed over a prolonged period of time are excluded from our study then there remain 4 ambulatory patients with chemical diabetes and 2 subjects with clinical diabetes. This represents a greater incidence of diabetes than expected if one compares the study group to the general population. Control studies on other inpatients in the Clinical Center and in a small series of patients with multiple sclerosis did not reveal any sign‘ificant glucose intolerance when they were studied in identical fashion to the patients wifi amyotrophic lateral sclerosis. It is difficult to ascertain the significance of the finding of some degree of carbohydrate intolerance in such a large percentage of patients with this illness. It is unlikely to be a major contributing factor in the pathogenesis of the illness as it is not uniformly present and its magnitude is not proportional to the severity of the neurologic disorder. It is important to be conservative in assessing the importance of these findings because similar studies in other illnesses have established a high incidence of “diabetes.” Subsequently, simple explanations of these findings have been offered in’ physical inactivity, poor diet, advanced age, etc. We have tried to explain our observations on these known variables and do not feel they are adequate. We believe that the data do demonstrate a chemical abnormality in the handling of glucose by the b,ody and this is found in’ an unusually and unexpectedly high percentage of patients with amyotrophic lateral sclerosis. This abnormality is not due to the defective utilization of sugar at the periphery (i.e., muscle) but is mediated through the pancreas as indicated by the failure to respond adequately to tolbutamide. The explanation of this abnormality in so many patients with amyotrophic lateral sclerosis is not apparent an’d warrants further elucidation. The association of amyotrophic lateral sclerosis with chemical diabetes has to be clearly distinguished from association of clinical diabetes with diabetic amyotrophy, a clinical entity characterized by a benign prognosis.21*22 ACKNOWLEDGMENTS Dietary Supervision, Miss Mary Ellen Collins; Mrs. Catherine Ahern, and Mrs. Maija Grinbush.
Technical Assistance, Miss Theresa Smith,
REFERENCES 1. Matthews, W. B.: Metabolic disease of the nervous system, clinical aspects. Proc. Roy. Sot. A. Med. X:859, 1958.
2. Sullivan,
J.:
Paper
on
diabetes
and
neurological diseases. Paper presented at the Boston Sot. Neurol. & Psy-
AMYOTROPHIC
chiat., 3. Fajans,
LATERAL
1961, S. S.:
1381
SCLEROSIS
personal
communication.
Diagnostic
Tests
for Dia-
betes Mellitus in Diabetes. Edited by Williams, R. H. New York, Paul B. Hoeber, 1960, pp. 389-422. 4. Conard, V.: Mesure de l’assimilation glucose, 1955. 5. Renold,
Acta
gastroenterol.
A, E., Martin,
Y. M., Steinke, and Sheps, M. small quantities tivity
using
proposed
rat
adipose
procedure.
39: 1487-1498, 6. Unger, R. H.,
J.
tissue Clin.
1960. and Madison,
1. a
L.:
betic
in mild subjects.
diabetic J.
Clin.
37:
627-630, 1958. 7. Blotner, H.: Effect of prolonged physical inactivity on tolerance of sugar. Arch.
Int. Med.
75.39,
175, 1963. 9. Bernard, C.: Lecons sur la Physiologic et la Pathologie in Systeme Nerveux, Vol. 1. Paris, J. B. Bailliere et fils, 1858, 397. 10. Izzo, J. L.: Interrelations of Diabetes
Edited
of the Liver, GastroinCerebrum in Diabetes.
by Williams,
P. H. New York,
Paul B. Hoeber, 1960, p. 666, 11. Himwich, H. E.: Brain Metabolism Cerebral Disorders. Baltimore,
of four
year
Oxford,
Massachusetts
of R. L.:
tolerance rics
and Wil-
liams and Wilkins Co., 1951, p. 33. 12. Jahnke, K., and Oberdisse, K.: Die Begutachtung des Zusammenhanges zwischen Trauma und Diabetes melli-
study
of
diabetes
J.A.M.A.
Decreased
in elderly
15:315-325,
15. Nissen,
H.
Sugar
152:
carbohydratr
patients.
A.,
and
Spencer,
W.:
tients
with
America 17. Balter,
40:887,
M.
Glucose
lO:lOO,
in pa-
Clin.
North
tolerance
curves
patients.
Dia-
1956.
neuropsychiatric
betes
mellitus
metabolism
cancer.
A. M.:
W. P. L., and
Diabetes
and carbohydrate
A,: New
1934.
A. S., Myers, R.
K.
in the arthritic.
Eng. J. Med. 210:13, Rawson,
Geriat-
1960.
tolerance
16. Glicksman,
in
L. P.:
town, re-
progress
1946-47.
86:
1953.
18. Ask-Upmack,
1945.
8. Buhr, P. A.: On the effect of prolonged physical inactivity on oral glucose tolerance. Helv. med. Acta 30:156-
and Diseases testines and
in a New England
the
14. Brand&
and nondiaInvest.
Wchnschr.
H. C. L., and Krall,
survey
Comparison of response to intravenously administered sodium tolbutamide
Med.
port
1322,
Invest. L.
1961.
Diabetes
18:655,
D. B., Dagenais,
Deutsch.
13. Wilkerson,
du
J., Nickerson, J. R., C.: Measurement of of insulin-like ac-
tus. 2358,
1961.
E.:
On
the
presence
of
deficiency factor in the pathogenesis of amyotrophic lateral sclerosis. A& med. Scandinav. 152:217-222, 19. Cumings, J. N.: Discussion of neuron Proc. 1024, 20.
Steinke,
disease-biochemical Roy.
Sot.
ured
aspects.
Med.
55:1023-
1962. J.,
Camerini,
and Renold, serum
A.
1955. motor
A. E.:
insulin-like with
the
rat
R.,
Marble,
Elevated
A.,
levels of
activity
as meas-
adipose
tissue
in
early untreated diabetes and prediabetes. Metabolism 10:707-711, 1961. 21. Locke, S., Lawrence, D. G., and Legg, M. A.: Am. J. Med. 34:775, 1963. 22. Garland, H: Diabetic amyotrophy. In Williams,
D.
(ed. ) : Modern
Trends
in Neurology. 2nd series. New York, Paul B. Hoeber, Inc., 1957.
lurgen Steinke, M.D., Instructor in Medicine, Haward Medical School, Boston, Mass.; Jr. Assoc. in Medicine, Peter Bent Brigham Hospital, Boston, Mass.; Research Assoc., Baker Clinic Research Laboratory, Boston, Mass. H. Richard Tyler, M.D., Senior Associate in Medicine, Peter Bent Brigham Hospital; Assistant Professor in Neurology, Harwrd Medical School, B&w, Mass.; Howard Hughes Medical Investigator.
B~JURGENSTEINKEANDH. Eleven of 13 consecutive patients with amyotrophic lateral sclerosis (ALS) exhibited an abnormality in glucose utilization, detectable by oral and intra-
abnormality persisted despite forced high carbohydrate intake and was present in patients with either severe or mild form of ALS. The explanation of
venous glucose tolerance tests and blood glucose
response
to tolbutamide.
this abnormality is not apparent.
This
MYOTROPHIC LATERAL SCLEROSIS (motor neuron disease) is a disease affecting motor neurons which is characterized by a subacute course ending in death. Recently a high incidence of abnormal glucose tolerance has been reportedly2 in these patients. It is the purpose of this study to document the existence of such a metabolic defect, and to clarify its tiature. Data will be presented on 11 consecutive patients with the clinical diagnosis and typical course of amytrophic lateral sclerosis. Carbohydrate metabolism has been assessed by oral and intravenous glucose tolerance, response to tolbutamide, sensitivity to exogenous insulin arid measurement of serum insulinlike activity. The results indicate a high incidence of chemical diabetes, apparently of pancreatic origin.
A
MATERIAL AND METHODS The clinical diagnosis of (motor neuron disease) amyotrophic lateral sclerosis was based on a history of a progressive neurologic deficit involving pyramidal tracts, motor nuclei, or anterior horn cells of the spinal cord. This was corroborated by objective findings of widespread involvement with spasticity, increased reflexes, muscle fasciculations, wasting and weakness.
In some patients
involvement ability.
there was primarily
of the spinal cord. All patients
bulbar
followed
involvement
the typical
and in others
The study took place over a 2 year period with 11 consecutive
tional patients
were not included
as they were long-standing
primarily
course with increasing
diabetics
patients. on therapy
dis-
Two addiin whom
neurologic symptoms and signs of amyotrophic lateral sclerosis developed. The patients were studied as inpatients at the Clinical Research Center of the Peter Bent Brigham Hospital. All patients bohydrate, the patients
received
supervised
a 3 day preparatory
by a dietitian.
were fed by gastric
tube.
diet consisting
If the oral intake The
following
of at least 250 Gm. of car-
was poor due to bulbar tests were performed
after
symptoms, an over-
From the Departments of Medicine and Neurology, Harvard Medical School and the Peter Bent Brigham Hospital and the Baker Clinic Research Laboratory, New England Deaconess Hospital, Boston, Massachusetts. These clinical studies were carried out in the Clinical Research Center of the Harumd Medical School and Peter Bent Brigham Hospital, supported by Grant 8MOl-FR-31-04 fl the National institutes of Health of the Department of Health, Education and Welfare; Public Health Gratis # FR-O.5185-01; T! AM 5077 New York. Received for publication Apr. 22, 1964.
and the Adler
Foundation
Inc.,
Rye,
1376 METABOLISM, VOL. 13, No. 11 (NOVEMBER), 1964
AMYOTROPHIC
night fast,
LATERAL
1377
SCLEROSIS
1 per day, in the following
order:
(1) oral glucose tolerance
test:
100 Gm. of
glucose were given orally and blood samples for glucose were collected fasting, at % hour, 1 hour, 2 hours and 3 hours. The blood glucose was determined by the autoanalyzer on venous blood. To be diagnostic for diabetes two or more of the following blood glucose levels had to be exceeded9 2 hours test; cent were Tho
fasting,
120 mg. and at 3 hours
100 mg. per cent,
a peak or at 1 hour of 160 mg., at
100 mg. per 100 ml.
(2)
Intravenous
glucose
tolerance
glucose in a dose of 0.5 Cm. per Kg. of actual body weight was injected as a 25 per solution within 3-5 minutes and venous blood samples for determination of glucose obtained fasting and starting from midpoint of infusion every 10 minutes for 1 hour. slope of the glucose disappearance was calculated according to Canard* and the value
K considered
to be abnormal
tivity was determined
if less than 1 per cent per minute.
after an overnight
sue assay where oxidation
of glucose
fast. The technic
labeled
in the C-l
(3)
employed position
Serum
insulin-like
ac-
was the rat adipose tisto Cr*Oa
is the index of
activity.6 All sera were assayed at a concentration of 2.5 per cent by dilution with buffer and reported as such in ,,LU per ml. (4) Intravenous tolbutamide response test; 1.0 Gm. of sodium tolbutamide
(Orinase@
period and samples
for blood glucose
sion every 10 minutes
Diagnostic)
was administered
obtained
fasting
for 1 hour. The blood glucose
intravenously
and starting
response
over a 3 minute
from midpoint
was considered
of infu-
to be abnor-
mal when the fall in blood glucose at 20 minutes was less than 25 per cent of the pretest (fasting) value and in addition at 30 minutes was less than 30 mg. per cent.6 (5) Sensitivity to exogenous
insulin;
crystalline
and samples for blood glucose preliminary
results
indicated
insulin,
glucagon-free
were collected
fasting
a great sensitivity
was injected
and every
to exogenous
rapidly
10 minutes
insulin
intravenously for 1 hour. AS
in the customary
dose
of 0.1 units of insulin per Kg. of body weight the dose was reduced to 0.05 units. At this dose the decrease in blood glucose was arbitrarily considered to be normal when a 25-50 per cent fall occurred
within 20-40
minutes
following
was in excess of 50 per cent and to be decreased
injection,
to be exaggerated
if the fall
if less than 25 per cent.
RESULTS
Of 13 consecutive patients with the clinical diagnosis of amyotrophic lateral sclerosis, 2 patients were excluded as they were known diabetics of many years duration. The remaining 11 patients denied symptoms of diabetes mellitus and there was no glycosuria on routine testing. As the oral glucose tolerance test is the accepted method of assessing glucose utilization and as interpretation varies, data available are presented in detail in table 1. By the outlined criteria for diagnosis of diabetes mellitus only 2 patients exhibited a normal curve, 1 a borderline diabetic curve and 7 showed typical diabetic values. Physical inactivity may deteriorate glucose tolerance,7J therefore it is noted if the patient, prior to admission, was ambulatory or confined to bed. Of the 7 patients who demonstrated glucose intolerance, 4 were ambulatory. Table 2 indicates the individual values of K for the intravenous glucose tolerance tests, the per cent fall of blood glucose within 20 minutes of injection of tolbutamide and the maximum per cent fall in blood glucose 20-40 minutes following administration of insulin, as well as the levels of serum insulin-like activity after an overnight fast. Table 3 summarizes the interpretation of each of the tests performed. Two patients, diabetic by oral glucose tolerance were judged nondiabetic by intravenous glucose tolerance test, and by response to tolbutamide. Both had signs of bulbar involvement and both had been fed by gastric tube. The remaining patients showed no discrepancy between oral and intravenous glucose tolerance. The tolbutamide response test followed
1378
STEXNKE
Table l.-Redb
AND
TYLER
of Oral Glucose Tolerance Tests in 10 Consecutive Patients with the Clinical Diagnosis of Amuotrophic Lateral Sclerosis
Patient
Age
C0Ulmellts
F
F. W.
56
Sex F
Bedridden
92
V.H.
31
F
Ambulatory
E. G.
c3
M
Bedridden
M. H.
55
F
Ambulatory.
*/ hr.
1 hr.
2 hr.
3 hr.
Interpretation
202
167
129
Diabetes
108
196 -
173
150
82
Diabetes
92
142
154
136
114
Diabetes
10 !i
2Od
163
122
71
Diabetes
114
210
218
164
47
Diabetes
7,;
236
294
124
64
Diabetes
M2
174
178
154
146
Diabetes
PlYSenCe of Severe Bulbsr symptoms
tube fed J.A.
61
M
Ambulatory
H. V.
56
F
Ambulatory, tube fed
LO.
49
F
Bedridden, tube fed
W. I’.
46
M
Ambulatory
102
164
165
118
104
Borderline
Slight
A.C.
48
M
Ambulatory
94
130
100
100
90
Nondiabetic
Minimal
I.A.
45
F
Ambu!atoru
P4
124
134
114
76
Nondiabetic
Minimal
Table 2.-Composite
Data on 11 Consecutive Patients with the Clinical Diagnosis of Amyotrophic Lateral Sclerosis -____-. ___-
_
IV Glucose
Patients F. W.
V. H. E. G.
_____
Tolerance Value K ___ 0.7
0.9 0.9
L. 0.
0.9 0.9 1.4 1.6
w. P.
0.9
A. C.
I. A.
1.3 1.5
E. B.
0.9
;A? H. V.
IV Tolhutamide
% Fall in Blood Glucoseat 20 min.
IV Insulin, Maximum Serum Insulin-like Activity in y0 Fall in Blood Glucose pU./ml. at 26% between 20 and 40 min.
11 18
66
40
-
13 23 14
66 69
75 -
26 27 25 26 25 23
22 41 35 66 .54 51 58 ..~~.___
100 130 so 120 55 65 6S 165 __. __-
_
closely the intravenous glucose tolerance. The values for serum insulin-like activity uncorrected for dilution exhibited a wide scatter ranging from 40 to 165 PU per ml., mean and standard error being 87 -t 13, respectively. Eensitivity to exogenous insulin in the administered small dose of 0.05 units per Kg. of body weight was cansidered normal in 2 patients, exaggerated in 7 and decreased in 1 patient. There was no relationship between insulin sensitivity, glucose tolerance and levels of circulating insulin-like activity. DISCUSSION
Since Bernard9 reported that a lesion in the floor of the fourth ventricIe can produce temporary glycosuria (piqure diabetique) there has been interest in the relationship between the central nervous system and carbohydrate metabolism. Although much experimental evidence has supported such an interrelationship,lO~ll lesions of the central nervous system rarely are responsible for the appearance of permanent diabetes in patients.12 On the other hand, diabetes has been reported to coexist with a variety of neurolagic disorders as well as with non-neurologic diseases. This is an expected observation as
AMYOTROPHIC
LATERAL
1379
SCLEROSIS
Table 3.-Comparative
Results and Znterpretation of Tests Performed Evaluation of Carbohydrate Metubolkm
Patients
F. W. V. H. E. G. M. H. J. A. H. V. L. 0. w. P. A. C. 1. A. E. B.
Oral
--___-_
GTT
Diabetes Diabetes Diabetes Diabetes Diabetes Diabetes Diabetes Borderline Nondiabetic Nondiabetic -
-___
IV GTT
Diabetes Diabetes Diabetes Diabetes Diabetes Nondiabetic Nondiabetic Diabetic Nondiabetic Nondiabetic Diabetic
IV Tolbutamide
Diabetes Diabetes Diabetes Diabetes Diabetes Nondiabetic Nondiabetic Nondiabetic Nondiabetic Nondiabetic Diabetic
fur
IV Insulin Sensitivity
Exaggerated
Exaggerated Exaggerated Decreased Normal Normal Exaggerated Exaggerated Exaggerated Exaggerated
diabetes mellitus is a common disease with an incidence of at least 2-3 per cent of the total population. la Furthermore, if the disease leads to physical in’activity this per se may deteriorate glucose tolerance. This often results in a state of chemical diabetes characterized by abnormal glucose tolerance but without symptoms of diabetes and not requiring treatment. In such instances, if return to physical activity is possible, glucose tolerance will also return to normal.7*8 In some patients, lack of a preparatory diet may be responsible for temporary glucose intolerance, known as starvation’ diabetes. Furthermore, age seems to influence glucose tolerance. I4 Therefore, it is of utmost importance that patients prior to any glucose tolerance testing are prepared by a high carbohydrate diet, that their age is stated and that the amount of physical activity is assessed. Failure to appreciate this may possibly be the cause for the extraordinarily elevated incidence of chemical diabetes detected in almost any chronic disease. For example, of 222 patients afflicted with arthritis, 57 per cent were found to have an abnormal glucose tolerance,15 similarly of 950 patients with cancer 37 per cent had abn.ormal values,lB of 767 neuropsychiatric ward patients 30 per cent showed a diabetic glucose tolerance.l? AskUpmack l8 found only 2 patients with diabetes in a small series with amyotrophic lateral sclerosis but it is obvi.ous that he discussed overt rather than chemical diabetes. Oti the other hand, CummingP commented that glucose tolerance was normal in 16 patients examined, however, he did not define normal nor present detailed data. In our series of 13 patients with amyotrophic lateral sclerosis, 2 had pre-existent overt clinical diabetes, requiring therapy.. There were 8 additional patients with chemical glucose intolerance as judged by inadequate response to glucose and tolbutamide although they lacked diabetic symptoms. Only 2 patients were unequivocally normal in this regard. All patients exhibited a gradual fall in blood glucose following glucose loading, however, the response of the abnormal group was typically delayed. Fasting values of serum insulin-like activity showed a wide scatter and statistically were not different from 30 normal control values, reported elsewhere.20 The itisulin sensitivity tests indicate that almost all patients with amyotrophic
1380
STEINKE AND TYLER
lateral sclerosis had an exaggerated response to exogenous insulin as the test dose was only half of the customary amount given. Therefore, an abnormal glucose tolerance test in these patients is unlikely to be due to a partial block of glucose uptake by the diseased muscle. Difficult to assess is the importance of bulbar involvement or immobilization in these patients. It remains conjecturable whether or not the bulbar lesion may be directly responsible for the abnormal glucose tolerance (piqure diabetique). There was some degree of correlation between bulbar signs and the presence or absence of the defect but the small number of patients make any conclusion hazardous. Many of the involved patients had normal activity and we believed it unlikely that physical inactivity in itself could account for our findings. If the patients confined to bed over a prolonged period of time are excluded from our study then there remain 4 ambulatory patients with chemical diabetes and 2 subjects with clinical diabetes. This represents a greater incidence of diabetes than expected if one compares the study group to the general population. Control studies on other inpatients in the Clinical Center and in a small series of patients with multiple sclerosis did not reveal any sign‘ificant glucose intolerance when they were studied in identical fashion to the patients wifi amyotrophic lateral sclerosis. It is difficult to ascertain the significance of the finding of some degree of carbohydrate intolerance in such a large percentage of patients with this illness. It is unlikely to be a major contributing factor in the pathogenesis of the illness as it is not uniformly present and its magnitude is not proportional to the severity of the neurologic disorder. It is important to be conservative in assessing the importance of these findings because similar studies in other illnesses have established a high incidence of “diabetes.” Subsequently, simple explanations of these findings have been offered in’ physical inactivity, poor diet, advanced age, etc. We have tried to explain our observations on these known variables and do not feel they are adequate. We believe that the data do demonstrate a chemical abnormality in the handling of glucose by the b,ody and this is found in’ an unusually and unexpectedly high percentage of patients with amyotrophic lateral sclerosis. This abnormality is not due to the defective utilization of sugar at the periphery (i.e., muscle) but is mediated through the pancreas as indicated by the failure to respond adequately to tolbutamide. The explanation of this abnormality in so many patients with amyotrophic lateral sclerosis is not apparent an’d warrants further elucidation. The association of amyotrophic lateral sclerosis with chemical diabetes has to be clearly distinguished from association of clinical diabetes with diabetic amyotrophy, a clinical entity characterized by a benign prognosis.21*22 ACKNOWLEDGMENTS Dietary Supervision, Miss Mary Ellen Collins; Mrs. Catherine Ahern, and Mrs. Maija Grinbush.
Technical Assistance, Miss Theresa Smith,
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