carbohydrate metabolism in addison's disease

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CARBOHYDRATE METABOLISM IN ADDISON'S DISEASE
George W. Thorn, … , Roger A. Lewis, Elizabeth F. Olsen
J Clin Invest. 1940;19(6):813-832. https://doi.org/10.1172/JCI101185.
Research Article
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CARBOHYDRATE METABOLISM IN ADDISON'S DISEASE1
By GEORGE W. THORN, GEORGE F. KOEPF, ROGER A. LEWIS,2 AND
ELIZABETH F. OLSEN
(From the Chemical Division, Medical Clinic, The Johns Hopkins University
and Hospital, Baltimore)
(Received for publication July 15, 1940)
Our understanding of the nature of the dis- means of synthetic desoxycorticosterone acetate
ordered carbohydrate metabolism in Addison's therapy.8
disease has advanced little since the original dem- METHODS
onstration by Porges in 1910 (1) of the frequent Before these studies were undertaken, normal subjects
occurrence of hypoglycemic reactions and the and patients with Addison's disease were maintained for
studies of Eppinger, Falta and Rudinger in which a period of 1 to 2 weeks on a standard diet of adequate
caloric intake. The ratio of carbohydrate: protein: fat
an increase in glucose tolerance was noted (2).
was kept constant. In most instances patients received
Subsequently, however, it was shown that patients
5.0 grams of carbohydrate, 1.3 grams of protein and 1.5
with Addison's disease developed marked symp- grams of fat per kgm. of body weight.
toms of hypoglycemia following the administra-
tion of small doses of insulin (3) and failed to Respiratory metabolism
show a rise of blood sugar as great as normnal During a preliminary period of 1 to 2 weeks, both the
subjects following the injection of a standard dose normal subjects and patients were trained for respiratory
metabolic studies. Expired air was collected for 10-min-
of epinephrin (4).
ute periods in a modified Baily gasometer and samples
Recently Long, Katzin and Fry (5) reported
were analyzed in duplicate for carbon dioxide and oxygen
in detail their studies relating to the effect of by means of a Haldane-Henderson gas analyzer. Differ-
adrenal cortical hormone on the carbohydrate ential derivation of calories was made with the aid of
metabolism of experimental animals. From their Lusk's table (6). In addition to determining the standard
metabolism after a 15-hour fast, the respiratory metabo-
own studies, as well as those of others, these
lism, blood sugar (7) and urinary nitrogen (kjeldahl)
authors concluded that "the administration of
were determined throughout the day at 2-hour intervals
cortical extract apparently decreases the propor- during a total fasting period of 22 hours. These de-
tion of glucose oxidized while there is an in- terminations were repeated following the injection of
creased proportion deposited as liver glycogen. adrenal cortical extract (Wilson, 50 cc.).4 The respira-
tory quotient, blood sugar and urinary nitrogen excretion
It is suggested that one of the properties of
. . . were determined at hourly intervals following the intra-
the cortical hormone is a stimulation of protein venous administration of glucose before and after treat-
catabolism and that the increased carbohydrate ment with adrenal cortical extract (50 cc.), desoxycorti-
levels, nitrogen and potassium excretion following costerone acetate (30 mgm.), corticosterone (85 mgm.),5
its injection into animals is an expression of this and 17-hydroxy-1l-dehydrocorticosterone (33 mgm.)
(Kendall's Compound E).5
effect."
A study of carbohydrate metabolism in un- Standard intravenous glucose tolerance test
treated patients with Addison's disease is difficult A test was adopted in which 0.5 gram of glucose per
because of the poor clinical condition of these kgm. of body weight was injected intravenously as a 20
patients. In the present study we have had the
8The synthetic desoxycorticosterone acetate used in
good fortune to be able to complete carefully con- this study was provided through the courtesy of Doctor
trolled metabolic studies on a limited number of E. Oppenheimer, of the Ciba Pharmaceutical Products,
untreated patients and on a larger number of pa- Inc., Summit, N. J.
4The adrenal cortical extract used in this study was
tients who were maintained in good condition by
supplied by Doctor David Klein of the Wilson Company,
Chicago, Ill.
1This study was aided by a grant from the Committee 5We are indebted to Doctor E. C. Kendall of the
on Research in Endocrinology, National Research Coun- MayoClinic,Rochester,Minn.,for the crystalline cortico-
cil. sterone and 17-hydroxy-l1-dehydrocorticosterone (Com-
2John D. Archbold, Fellow in Medicine. pound E).
813
814
GEORGE W. THORN, GEORGE F. KOEPF, ROGER A. LEWIS, AND ELIZABETH F. OLSEN
per cent solution in distilled water. The flow was ad- 80mgm. per 100 cc. (166determinations). These
justed so that the infusion was completed in 30 minutes. observations confirm earlier studies (9, 10).
This rate of glucose administration (0.5 gram per kgm. Treatment with adrenal cortical extract (Wil-
per % hour) approximated the maximum rate of in-
testinal absorption of glucose and hence provided an son, 4 to 10 cc. daily, injected subcutaneously)
intravenous glucose test which was within physiological was associated with an appreciable rise in the
limits. Capillary blood for sugar determinations was average fasting blood glucose level (Table I).
taken in the fasting state and at 30-minute intervals dur-
ing a4-hour period following the glucose infusion. Urine
TABLE I
specimens were collected at appropriate intervals and
analyzed for sugar. Effectofadrefnaaslticnorgtibclaolodhogrlumcoonsee therapyon
Oral glucose tolerance test (Addison's disease)
A solution of glucose, 1.75 grams per kgm. of body
weight, was given. Capillary blood for sugar deter- Fastingbloodgluose(sg.paf100c;)
minations was taken during the fasting state and 30, 60,
120 and 180 minutesEapfitneerphthreinintgeessttion of glucose. tWmreereaotrn-ot Dtceeeortxoayntteeo (Acienodxjrrtetreciantccaedtdla)l Aeo(dxorrtrterainlcaa)atll Cjoteer(trtIeoo-ndoe). 11(7tW-tihoirydncdoerrnotOx)y-
minajEsepsciatngeedepdhsruivbnic,guotr0a.on0ue0so7luysmlgfyo.mr.aTphepreerkisgoimtde.oofoff2tbhomeidnyiuntwjeeesic.gthiotnC,apwwiaalss- 5(Np_ua_mt_be_net_rs_o_f__de_- 76 3-~~2d7a07lgz. 4-d1a8i01lcc. 8-da18i23lc. __ _33_i__
lary blood for sugar determinations was taken during teminatIons). (43) (60) (20) (30) _
the fasting state and 15, 30, 60 and 90 minutes after the PatentE.L.. 75 75 84 99 95
injection of epinephrin. Rage.. (6-81) (72-81)
Includesvaluesobservedduringtreatment witheither
OBSERVATIONS daily intramuscular injection of a solution of hormone in
Increased appetite for carbohydrate oil, or subcutaneously implanted pellets of crystalline
desoxycorticosterone acetate.
It is of interest to note that many patients with tMassive dose, 50-70cc., duringa 24-hourperiod.
Addison's disease had formed the habit of
sup- The oral administration of larger quantities of
plementing their regular diet with intermediate
adrenal cortical extract in glycerol solution (8 to
nourishment of foods containing readily available
12 cc. daily, 1 cc. representing 50 grams of
carbohydrate (Patient E. L., see protocol). In adrenal gland) was likewise associated with a rise
this respect there is a parallel to the increased in the average value for fasting blood glucose.
appetite for salt and salty foods which has been
Treatment with large quantities of adrenal corti-
noted clinically by many observers, and confirmed cal extract (Wilson, 20 to 50 cc. daily, injected
experimentally by the studies of Richter and
subcutaneously and intravenously), corticosterone
Eckert on adrenalectomized rats (8). (85 mgm.) and 17-hydroxy-11-dehydrocortico-
sterone (33 mgm.) in oil, injected intramuscularly
Fasting blood glucose
in divided doses, was followed by a much greater
The fasting blood glucose level of untreated elevation in fasting blood glucose level (Patient
patients with Addison's disease was observed to E. L., Table I).
be in the low-normal range in most instances. In The efficacy of treatment with adrenal cortical
a group of 20 patients the average blood glucose extract (50 to 70 cc.) in preventing the gradual
value a (108 determinations) was observed to be fall in blood glucose during a prolonged fast is
80mgm. per 100cc. before treatment. Prolonged illustrated in Figure 1. The rise in blood glucose
treatment with desoxycorticosterone acetate did which reached its maximum 6 to 8 hours after
not affect the fasting blood glucose level since the injection of extract did not appear to be due to
average value observed during treatment was also traces of epinephrin which may have been present
in the extract, since there was no immediate rise
*All blood sugar values determined by the modified
micromethod of Folin and Malmros are arbitrarily re- in blood glucose as might have been anticipated
ferred to in this study as "blood glucose values." following an injection of epinephrin.
CARBOHYDRATE METABOLISM IN ADDISON S DISEASE 815
M.B. bNo treatment
"01
-~M Adrenal Cortical
ADD/5ON'3 DI3EA3
Blood 100 extract
Glucose Ex+ract
Mgc. 80 _I
per
I,---___________------7
00OO'C.C
401
o0
0
Hours
I5 18 21
FIG. 1. EFFECT OF ADRENAL CORTICAL EXTRACT ON BLooD GLUCOSE LEVEL
(PROLONGED FAST)
Oral glucose tolerance significance in the response of patients with Ad-
dison's disease. At the time of initial examina-
The striking intolerance of patients with Addi-
son's disease to the oral administration of glucose tion, approximately 75 per cent of a group of 30
is well known (11). Not infrequently an adrenal patients with Addison's disease were found to
crisis has been precepitated by this test. have an abnormal oral glucose tolerance curve.
A comparison between the blood glucose values The symptoms of pylorospasm which so fre-
of 8 control subjects and 4 untreated patients with quently followed the oral administration of glu-
Addison's disease following the oral administra- cose to these patients suggest that the apparent
tion of glucose, is shown in Figure 2. The low- increase in glucose tolerance (flat-type of curve)
normal initial fasting sugar level, the " flat-type" was in a large measure due to an abnormality in
of glucose curve, and the striking hypoglycemia the intestinal absorption of glucose. This- was
which was frequently noted 2 to 3 hours follow- confirmed by the normal height to which the blood
ing the administration of glucose are of particular glucose level rose following the intravenous ad-
BLOOD
--
GLUCOSE
MG. i5o
perp
*100
CC.
125
10C .)
75
50
25 _
0
MINUTE5 0 60 12O 180
FIG. 2. ORL GLUCOSE TOLERANcE TEST
816 GEORGE W. THORN, GEORGE F. KOEPF, ROGER A. LEWIS, AND ELIZABETH F. OLSEN ,.
4 PATIENTS .-- BEFORE TREATMENT
ADDISON'S DISEASE ..ee... AM1R TREATMENT
175 [AVERAGE DURATION OF3
kTREATMENT-IYEAR I
BLOOD
GLUCOSE
MG 150
PER
100CC 4? .
125 0*
S*
iS0*Xf"'40*@%SS@9*0S@000006% 90
*0 *%96
oc
I-~~~~~~~~~~~~1a
75
50
25
A
M-INUTES 0 60 120 186
FIG. 3. ORAL GLUCOSE TOLERNCE TEST. THE EFFECT OF
DESOXYCORTICOSTERoNE TREATMENT
ministration of a standard dose of glucose (see improved at the time the second glucose curve
Figure 5). was determined. It would seem likely that the
Following prolonged treatment (1 year or change in the glucose curve was due primarily to
more) with desoxycorticosterone acetate, we ob- improved absorption of glucose from the intes-
served a marked change in the oral glucose toler- tinal tract and not to a marked or specific effect
ance curve in 4 patients (Figure 3). The clini- of desoxycorticosterone acetate on the internal
cal condition of these patients was markedly metabolism of glucose, inasmuch as desoxycortico-
______5-18--40
J.B. ......::*se
3-50-40
BLOOD 500
GLUCOSE
MG. 250 S
per'
too CC. ° V.
200
150
5o0o,
0
MIbJUTES 0 50 60 90 120 150 180 210 Z40
FIG. 4. INntAvENOUS GLUCOSE TOLERANCE TEST
NORMAL SUBJECT
817
CARBOHYDRATE METABOLISM IN ADDISONS DISEASE
BLOOD
GLUCOE.
MG. 200
IOOC.C. s
175
ISo
SZ5
50
141NINTES30 60 90 120 150 180 210 240
FIG. 5. INTAVENous GLUCOSE TONCE TEST IN PATIENTS WITH ADDISON'S DISEASE
sterone acetate therapy had no demonstrable effect TABLE II
on the blood glucose curve following the intra- Intravenousglucose tokranc curve
venous administration of glucose.
PATIENTS WIVTH ADDISON'S DISEASE
Intravenous glucose tolerance
In order to eliminate the obvious disadvantages Pa- Sex Age Bloodglucose (mgm.per100cc.)
tient
oifntgrlauvceonsoeusadgmliunciossteerteodleorraanlcley,tweset u(sseedeamestthaonddsa)r.d Fg um3it0neus- um4ti5ens- um6ti0ens- um9ti0ens- um1ti2en0s- um1ti5en0s- um1it8ne0.s- um2ti4en0s-
One consideration seemed essential, viz., that the F.H. M 21 77 210 182 163 123 86 65 50 48*
rate of glucose solution introduced intravenously Y.E. F 39 79 225 177 120 118 84 66 59*
S.W. F 55 111 426 235 171 100 77 69*
should not exceed the maximum rate of intestinal J.P. M 21 79 270 202 192 163 99 75 62*
M.B. F 31 78 250 135 77 56 48* 61*
absorption of glucose, if physiological studies were 0E..0L.. FM 4513 7786 224315 118832 115430 110030 7774 5612 5500**
to bemade. Experience now indicates that, under A0..QH.. MM 3629 8819 241 182 114409 111138 9702 6716* 68 62
constant conditions, the blood glucose curve fol- AB.WS.. MM 2336 8768 220604 211654 113916 114052 18054 8686 6692 6797
lowing the intravenous administration of 0.5 S.P. M 27 80 206 156 105 80 68 60 72
A.H. F 20 78 222 194 164 131 97 70 60 64
of glucose kgm. of body weight during H.H. M 38 99 254 225 153 112 104 78 78 80
gram per
a 30-minute period is constant for a given indi-
vidual (Figure 4). NORMAL StBJIECTS
Patients with Addison's disease frequently de-
F.A. M 23 81 282 204 164 88 67 69 82 106
veloped marked symptoms of hypoglycemia 2 to 3 A.K. M 23 84 194 91 78 71 76 84
C.D. M 26 89 220 123 70 55 78 80 84 87
hours after the administration of glucose intra- R.L. M 28 95 290 202 164 106 75 73 64 68
S.A. M 25 87 220 155 110 81 76 83 81 78
venously (Table II). In some patients coma and
vasomotor collapse occurred and additional glu- * Hypoglycemic reaction.
818 GEORGE W. THORN, GEORGE F. KOEPF, ROGER A. LEWIS., AND ELIZABETH F. OLSEN
F- u~~~~~~~~~~I
usU
~~~!j - [ 8
o -
0
(Zo <
~o~-
0~~~~~
z~~
x
WV~~~~SW'
0~~~~~~~
u 8~~~~
or ~ *o
a-~~~~~~~~~~~a
tA*~~~~~~~~~~
~~~ hi~a
0~~~~
Z~~~~~~~~
j ). ig~~~
hi
z
CARBOHYDRATE METABOLISM IN ADDISONS DISEASE 819
cose by vein and orange juice by mouth were hydroxy-11-dehydrocorticosterone (33 mgm.) or
required. However, this marked disturbance did large doses of adrenal cortical extract (50 to 70
not occur in all patients with Addison's disease cc.) completely prevented the appearance of symp-
(Figure 5). In the patients with the "carbo- toms of hypoglycemia and, in addition, increased
hydrate defect," three changes were of particular the blood glucose level throughout the test. Nor-
interest: (1) the ease with which hypoglycemia mally, glycosuria was never observed during the
was precipitated; (2) the severity of the symp- glucose tolerance test of patients with Addison's
toms and the great difficulty which was experi- disease. Following treatment with large quanti-
enced in spontaneously recovering from the in- ties of adrenal cortical extract, 17-hydroxy-11-
duced hypoglycemia; and (3) a definite lowering dehydrocorticosterone and corticosterone, glyco-
BBLLUOCOODSE
MG
PER
100C.C.
MINUTES 0 50 60 90 120
FIG. 7. RESPONSE TO EPINEPHRIN
of the threshold at which symptoms became mani- suria occurred during the standard intravenous
fest, since untreated patients with Addison's dis- glucose tolerance test.
ease frequently developed marked symptoms of
hypoglycemia at a blood glucose level which did Epinephrin test
not produce symptoms in normal subjects.
Treatment with certain adrenal corticalhormone The decreased glycemic response of patients
preparations (large quantities of adrenal cortical with Addison's disease to a standard dose of
epinephrin is illustrated in Figure 7. It is also
extract, corticosterone and 17-hydroxy-11-dehy-
drocorticosterone) was followed by an increase in of some interest to note that the injection of
the fasting blood glucose level, an increase in the epinephrin during the hypoglycemic reaction pre-
height of the glucose curve and an absence of cipitated by the standard intravenous glucose tol-
signs and symptoms of hypoglycemia (Figure 6). erance test was followed by a prompt but tem-
Desoxycorticosterone acetate (30 mgm.) treat- porary rise in blood sugar level associated with a
ment ameliorated the symptoms of hypoglycemia temporary remission inthe hypoglycemic signs and
but did not affect the blood sugar level; cortico- symptoms (Figure 8). The immediate and tran-
sterone (85 mgm.) both ameliorated the symp- sient effect of epinephrin in raising the blood
toms and delayed their onset; treatment wuth 17- glucose level is in marked contrast to the slower
820 GEORGE W. THORN, GEORGE F. KOEPF, ROGER A. LEWIS, AND ELIZABETH F. OLSEN
BLOOD
GLUCOSE
MG
per
100 C.C.
MINUTES 0 50 60 90 2a0 Is* I8O 210 t40
FIG. 8. INTRAVENOUS GLUCOSE TOLEANCE TEST (ADDiSON's DISEASE)
and more prolonged action of adrenal cortical the test without supplementary glucose therapy.
hormone (4 to 24 hours). The limited quantity of crystalline hormone avail-
In one patient the response to epinephrin fol- able did not permit an exact determination of
lowing an overnight fast was observed in the equivalent quantities of adrenal cortical extract
untreated state and again after several days of and crystalline 17-hydroxy-11-dehydrocortico-
treatment with adequate doses of adrenal cortical sterone.
hormone (20 cc. daily, injected subcutaneously). Standard metabolism
Associated with treatment there was a small but
The standard metabolism of patients with Ad-
definite increase in the height of the blood glucose
dison's disease has been considered to be definitely
curve, an increment of 27, 15, 11, 3 mgm., re- lower than that of normal subjects. The values
spectively, at 15, 30, 60 and 90 minutes following
which were obtained in 15 untreated patients are
the subcutaneous injection of epinephrin (see
given in Figure 9. In our experience a basal
methods).
Response to insulin
Because of the profound reaction of patients
-l .,
with Addison's disease to relatively small doses
of insulin, we did not study the action of this
hormone in human subjects. In bilaterally ad- 0
renalectomized dogs (to be reported elsewhere),
it was demonstrated that treatment (6to 18 hours
beforehand) with 50 to 80 cc. of adrenal cortical
extract completely prevented the severe and often
fatal hypoglycemic reaction which followed the -20 0
intravenous injection of 0.25 units of insulin per
kggm. Large quantities of desoxycorticosterone
-so
acetate (50 mgm. or more) were ineffective in
preventing convulsions. Treatment with 17-hy-
-40'
droxy-11-dehydrocorticosterone, however, in a
FIG. 9. BASAL ME-TABouc RATE IN 15 PATIENTS WITH
dose of 10 mgm., permitted the animal to survive ADDISON'S DISEASE (UNTREATED)
-CARBOHYDRATE METABOLISM IN ADDISONS DISEASE 821
PATIENT E.L.
L
o
B.M.R.
IL
-10l II II1
DAYS I 20 50 35 +0 45 50 55 60
tO is 25
CORTICOSTERONE 17-lHYDROXY-I1-
85 MG DEHYDROCORTICO-
STERON£
33 MG.
FIG. 10. THE EFFECT OF ADRENAL CORTICAL HORMONE TREATMENT ON BASAL METABoLIc RATE
(ADDISON's DIsEASE)
metabolic rate lower than -20 per cent is un- TABLE III
usual in patients with Addison's disease uncom- Standard respiratory quotient
plicated by thyroid pituitary deficiency. (Constant dietaryregimen)
or
In of 7 patients, significant change
a group no
in the average basal metabolic rate was noted fol- ADDISON'S DISEASE
lowing continued treatment with desoxycortico- Patient Sex Age Weight Respiratoryquotient
sterone acetate. The average value before treat-
kgm.
ment was 10 per cent (18 determinations) and E.L.... F 51 48 0.92,0.90,0.93, 0.91, 0.85, 0.87,
during treatment 12 per cent (10 determina- J.P... M 21 45 00..9900,,00..9902
tions). However, treatment with corticosterone M.B... F 31 48 0.88,0.86,0.86,0.87
Y.E... F 39 54 0.90
or 17-hydroxy-11-dehydrocorticosterone was fol- O...O. M 43 59 0.92
lowed by significant rise in the standard metab- A.S... M 33 57 0.87, 0.92,0.87,0.86
a
S.P. M 27 70 0.86,0.83,0.79
olism of Patient E. L. (Figure 10). A.H... F 20 57 0.85,0.86,0.83,0.84
Standard respiratory quotient Weighted average 0.88
A comparison between the standard respiratory
NORML SUBJECTS
quotient of 6 normal subjects and 8 patients with
Addison's disease revealed no significant differ- F.A.... M 21 60 0.89
S.A.... M 23 81 0.84
ence between the average of the two groups R.L... M 28 75 0.82,0.82,0.80
(Table III). However, if the values for 3 pa- C.D... M 26 84 0.85,0.86
V.H... F 30 47 0.87
tients (S. P., A. H., and A. S.) who were ob- J.B.... F 37 58 0.88, 0.86
served to have no demonstrable abnormality in
carbohydrate metabolism (see intravenous glucose Weighted average 0.86
tolerance tests, Table II) are excluded, the aver-
age value for the group of patients with the quantities of adrenal cortical extract (20 to 70
carbohydrate-defect" is approximately 0.90. cc.) corticosterone (85 mgm.) or 17-hydroxy-11-
"
This value is significantly higher than the value dehydrocorticosterone (33 mgm.) was followed
for the group of control subjects. by a striking reduction in the standard respiratory
Prolonged treatment with desoxycorticosterone quotient when treatment was instituted 12 to 18
acetate (maintenance dose) had no effect on the hours preceding the test (Patient E. L., Table
standard respiratory quotient of 3 patients (E. L., IV). The reduction in standard respiratory quo-
A. H., M. B., Table IV). Treatment with large tient was accompanied by a rise in fasting blood