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or desiccated thyroid in physiologic dosage
Hydrocortisone and/or Desiccated Thyroid in Physiologic Dosage XIII.
Carbohydrate Metabolism Dosage Thyroid (Proloid)
during Large Therapy
BZJT. S. DANOWSKI, J. V. BONESSI, M. E. SANER A battery of tolerance tests which reflect carbohydrate metabolism (glucose, insulin, tolbutamide, acetohexamide and epinephrine) through changes in the levels of the blood sugar and serum inorganic phosphorus were largely unaffected by purified desiccated thyroid (Proloid) therapy which reached dosages of 25 grains per day in successive increments. Tentative interpretations are advanced to explain the few statistically significant changes that were induced by the administration of these large dosages of desiccated thyroid. Judging from blood sugar values the J-hour glucose tolerance test was not altered by these large dosages of desiccated thyroid but such treatment was associated with a more prompt return of the serum inorganic phosphorus to or above the starting levels. The lessened hypophosphatemia during the glucose tolerance test observed in the course of dosage thyroid therapy could reflect decreased use of phosphorus in glycolysis, diminished segregation as a consequence of the formation of ATP, or enhanced deposition of glycogen without phosphorus in depleted tissues, alone or in combination. The equivalent but shortened hypoglycemic response to exogenous irsu-
S
PONTANEOUS creased
of diabetes
now more than 2 decades
in man
mellitus.
old hut based
C. MOSES
lin observed during thyroid feeding was not accompanied by a more prompt return of serum inorganic phosphorus levels to the preinsulin values. Evidence from other studies that the biologic halflife of insulin is shortened by thyroid hormone excesses prompts the suggestion that this is responsible for the shortening of the hypoglycemia, but this does not explain the failure to observe a comparable shortening of the hypophosphatemic response to insulin. Trends to increased hypoglycemic and hypophosphatemic effects of tolbutamide and acetohexamide during thyroid hormone excesses could reflect islet cell hyperfunction or hyperplasia induced, perprior thyroid feeding haps, during secondary to a shortening of the biologic half-life of insulin. The usual hyperglycemic-hypophosphatemic responses to exogenous epinephrine were enhanced by large dosages of desiccated thyroid, suggesting that despite such therapy hepatic and other glycogen stores were intact and readily mobilizable. It ma} be that the first response to thyroid hormone excesses is an enhancement of glycogenolysis and that glycogen depletion is a subsequent event.
THYROTOXICOSIS
prevalence
AND
is associated
The data of Regan
on 1,883 patients
with
an in-
and Wilde+
with hyperthyroid-
740
DANOWSKI, BONESSI, SARVER AND MOSES
ism indicated the prevalence of diabetes mellitus in hyperthyroidism to be 3.2 per cent. This composite figure was derived from a 1.7 per cent frequency in patients with exophthalmic toxic goiter and a 5.6 per cent frequency in those with toxic thyroid adenomata. Opportunities to test carbohydrate metabolism prior to the onset of spontaneous thyrotoxicosis are limited. We have therefore undertaken by means of various tolerance tests to quantitate carbohydrate metabolism in a group of healthy adult prisoners prior to and while receiving a purified preparation of desiccated thyroid (Proloid), 25 grains per day. MATERIALS Blood
sugar
and serum
inorganic
AND METHODS
phosphorus
responses
to oral
glucose
and to intra-
venous insulin, tolbutamide, acetohexamide and epinephrine were determined in 10 healthy young adult prisoners between the ages of 22 and 51 years. In each case the test was initiated between 6:30 and 7:00 a.m. following an overnight fast. Except during the epinephrine tolerance the subjects sat quietly without smoking. The epinephrine test, however,
was performed
The glucose
with the men lying on a bed.
was ingested
per Kg. of body of body weight,
weight.
as a 56 per cent solution in water
In the insulin tolerance
was injected
intravenously
test regular
at a dosage
of 1.75
insulin, 6.1
unit per
at zero time immediately
0.9 per cent saline solution for ease of measurement.
A standard
after
dilution
Gm. Kg. with
dose of sodium tolbut-
amide, 1.0 Gm., in 20 ml. of distilled water, was infused intravenously during a 2 to 3 minute intervalsarb The same dosage and procedure were followed with acetohexamide,sc save that a 2.5 per cent solution in phosphate
buffer
(inorganic
phosphorus
concentration
of 79 mg. per cent) was used. The epinephrine tolerance test was based upon the subcutaneous injection of 0.01 unit of a 1:lOOO commercial solution of epinephrine hydrochloride per Kg. of body weight administered in 3 equal parts at zero, 10 and 20 minutes. Samples
of venous
serum inorganic
blood
phosphorus
lowing the administration
were
withdrawn
(Fiske-Subbarow)
for
blood
sugar
(Hagedorn-Jensen)
analysess”se prior to and at intervals
and fol-
of the test material. RESULTS
A. Glucose
Tolerance
Tests
In the oral glucose tolerance test the ingestion of 1.75 Gm. of the sugar per Kg. of body weight produced comparable hyperglycemia prior to and during the ninth week of therapy with desiccated thyroid in increasing dosages which had reached 25 grains per day at the time of tolerance test. In neither test was there any delay in the disposal of the glucose load, judging from the peak and the 2-hour blood sugar values. In each group a distinct hypoglycemic tail was evident at or beyond the second hour (table 1) . Although the mean decreases in inorganic phosphorus during the glucose tolerance (table 2) were less in the first 3 hours of the test conducted during the ingestion of 25 grains of desiccated thyroid, the differences between these decrements and those recorded in the control period were not statistically significant. However, in the fourth and fifth hours of the glucose tolerance test conducted during the treatment period the serum inorganic phosphorus rose distinctly above the starting level, while during the same segment of
CARBOHYDRATE
XIETABOLIS,M
Table l.-Blood
AND
THYROID
741
THERAPY
Sugar Values (mg. %) during Various Prior fo and during Thyroid Therapy
Tolerance
Tests
__.~
___~~_.
Control Mean F S.D.
Oral
o-o.5 hr.
glwnst~:
39.4 i- 29.4 6.6 t 16.7 -6.2 t 15.9
O-l.0 hr. O-2.0 hr.
-11.8 -12.2 -8.2
?I 19.0 -c 7..5 fr 6.5
10 10 10 4
-.53.7 -31.2 -19.6 -7.2
t t + -ir
H 8 8 8 8 8
-26.6 -375 -28.0 -IS,.5 -13.9
O-3.0 hr. o-4.0 hr. O-5.0 hr. Inwlin:
O-0.5 hr. O-1 .O hr. O-l.rj hr. O-2.0 hr.
Tolhutamidc:
O-15 O-30 O-45 O-60 O-90
min. min. min. min. min.
O-120
Thyroid: Mean
min.
-6.4
i- 14.5
-4.2 -10.0
i- 18.3 -c 15.2
15.2 10.1 17.7 6.7
A9.5 -20.0 -10.6
k t t
t
10.1
t t t t
8.1 13.6 3.x 10.5
-30.5 -31.2 -33.2 -23.0 -15.0 -19.1
-t 18.1 I!Z 8.9 t 11.8 f 12.6 -t- 12.8 i 11.0”
-0.8
k 4.1
10.3 13.1° Il.6
-t 9.1
- “7.1
i 7.3
-:3.3.0
-c 16.l)
-31.4 -32.9 -24.2 -1o.F;
i +_ t i
-%3.2 -:34.6
i l-1,.3 & 10.3
-16.9
i- 10.3
--33.1 -21.6 -23.Fi
-4 S.5 t Il.4 i- 8.4
x 8
O-4.5 min. O-60 min. O-90 min. O-1 20 min.
8 8 8 8
n-o.5 hr. O-1.0 hr.
7 7
31 .o : 9.7 27.4 ri 9.6
O-l.5 hr. O-2.0 hr.
7 7
18.3 -c 10.9 lFi.0 IL 17.0
min.
36.4 -+ 21.3 3.6 +- 29.5 2.3 -t 13.0 -6.6
O-30 min.
O-l.5
25 grains/d t S.D.
7.3 10.7 8.6 .5,6
“5.0 1 13,s 36.1 -+ 10.8” 22.6 k 16.0 10.3 -c 9.2
*Paired I-tests: p < .I%, the control Thus
tolerance
the phosphorus
at 5 hours the mean
per cent.
The
less than
0.01).
H. Insulin Even
difference
Tolerance though
duration
by the ingestion
of the response from
parison
of the differences
The
the blood
decreases
insulin
ment phases.
these
2 means
sugar
of large
levels
between
tests
The slight
response
was distinctly
in serum
tolerance
in the 2 tests were
to its zero value.
fO.91
and
is statistically
-0.01
mg.
significant
(11
Tests
judging
the
between
the hypoglycemic
was not affected
had not yet returned
changes
at 1 hour
during
present
point
thyroid,
treatment
were the
at that
com-
point).
of equal
control
the
period,
(11 less than 0.05 upon values
phosphorus
conducted
at the 30 minute
of desiccated
less in the thyroid
the mean
inorganic
differences
to insulin dosages
and
were not statisticallv
magnitude thyroid
iI1
treat-
significant.
742
DANOWSKI,
Table B.-Serum .~
BONESSI,
SARVJZR AND
MOSES
Znorganic Phosphorus Changes during Various Tolerance Tests Prior to and during Thyroid Therapy Subjects (if)
Control Mean 2 S.D.
Thyroid: 25 grains/d Mean Y? S.D.
Oral glucose:
O-O.5 hr. O-l .O hr. O-2.0 hr. O-3.0 hr. 04.0 hr. O-5.0 hr.
4 5 4 5 5 5
-0.69 -0.96 -1.16 -0.63 -0.24 -0.01
+ t f + -t *
0.5 0.7 0.4 0.4 0.5 0.4
-0.47 -0.56 -0.73 -0.29 0.45 0.91
ir t * 3: * -t
0.2 0.1 0.3 0.4 0.4 O.lf
Insulin:
O-O.5 hr. O-l .O hr. O-l.5 hr. O-2.0 hr.
10 10 10 3
-1.60 -1.27 -0.86 -0.40
X!X0.4 k 0.5 t 0.5 * 0.2
-1.59 -1.20 ---0.71 --0.67
-c f t -t
0.3 0.5 0.5 0.5
Tolbutamide:
O-15 min. O-30 min. O-45 min. O-60 min. O-90 min. O-120 min.
8 8 8 8 8 8
-0.33 -0.68 -0.87 -0.71 -0.63 -0.62
-+ + -c * t f
--0.75 -1.15 -1.26 - 1.39 -1.34 -1.24
2 -+ .t c t rt
0.3 0.5 0.4 0.6* 0.6* 0.7
Acetohexamide:
O-15 min. O-30 min. O-45 min. O-60 min. O-90 min. O-120 min.
8 8 8 8 8 8
-0.03 & 0.4 -0.47 zk 0.5 -0.84 t 0.4 -0.94 -t 0.4 -0.76 + 0.4 -0.67 f 0.4
-0.45 k 0.6 -1.23 + 0.3’ -1.38 t 0.6 -1.49 k 0.6 -1.45 -t 0.7’ -1.19 Xk 0.v
Epinephrine:
O-O.5 O-1.0 O-l.5 O-2.0
7 7 7 7
-0.48 -0.63 -0.36 -0.55
-1.42 -1.05 -0.61 0.33
“Paired tP
<
t-tests:
hr. hr. hr. hr.
-c i k 2
0.4 0.4 0.4 0.4 0.4 0.4
0.1 0.2 0.6 0.1
+ & + t
0.5” 0.4 0.3 0.4
p < .05.
.Ol.
C. Tolhutamide
nnd Acetohexamide
Tolerance
Tests
There is a suggestion that during thyroid feeding these 2 drugs were more effective in producing hypoglycemia, but this trend, insofar as the blood sugar responses are concerned, reached statistical significance only at the 2-hour point of the tolbutamide tests. Further support for this view can be adduced, however, if the serum inorganic phosphorus changes are taken into account. These indicate that with both drugs thyroid feeding enhanced the usual hypophosphatemia at several points during the tolerance test (table 2). D. Epinephrine
Tolerance
Test
The daily ingestion of 25 grains of desiccated thyroid was associated with but two changes in the response to subcutaneous epinephrine: the hyperglycemic response at 1 hour was enhanced and the hypophosphatemia at the half-hour point was greater.
CARBOHYDRATEMETABOLISM AND THYROIDTHERAPY
743
DISCUSSION The absence of a striking effect of these large amounts of desiccated thyroid upon various indices of carbohydrate metabolism may be related to the dosage, the duration of therapy, the characteristics of the thyroid hormone preparation or the nonsusceptibility of the subjects. With regard to the first two of these obviously spontaneouus thyrotoxicosis may be more severe and of much longer duration than was the hyperthyroidism-induced in this study. These factors could account for our failure to observe any diabetogenic action of the purified desiccated thyroid preparation. It is unlikely that any special quality of this purified and standardized preparation of desiccated thyroid was responsible for the absence of a diabetogenie effect, though this has not been tested. Insofar as the susceptibility of subjects of these studies is concerned, it is, of course, true that diabetes mellitus is less frequent in youth and that the highest coincidence of thyrotoxisis and diabetes mellitns occurs in patients older than the subjects used in this study. The data presented do suggest, however, that large dosages of desiccated thyroid are not immediately diabetogenic. As a matter of fact in vitro studies indicate that thyroid hormone facilitates the disposal of glucose.““-fI Hence the occurrence of diabetes mellitus in a previously nondiabetic subject and the aggravation of existing diabetes mellitus by excesses of thyroid hormone must be sought in other mechanismsSa It is possible, for example. that the increased intake of food which characterizes spontaneous thyrotoxicosis ultimately exhausts the insulinogenic reserves of the pancreas with or without affecting the levels of effective insulin. Also, the increased absorption of foodstuffs, and of sugar in particular, from the gut which characterizes thyrotoxicosis might raise the peak levels of blood sugar and thereby make further demands upon insulin secretion. In a patient with known diabetes mellitus the increased reabsorption of filtered glucose by the kidney could have a similar effect. Furthermore the marked decrease in hepatic glycogen produced by thyroid hormone excesse+J could be expected to decrease carbohvdrate tolerance, since these circumstances evoke a mobilization of depot fat and ketone body production.i8 Again in established diabetes mellitus one might anticipate that such deglycogenation would render more difficult the regulation of carbohydrate metabolism, induce shocking, and thereby modify the insulin requirement. Finally, it is possible that thyroid hormone accelerates the destruction of insulin.hX One must conclude therefore that it is a sum total of these and other unidentified diabetogenic factors evoked secondary to thyroid hormone excesses that is responsibIe for the higher prevalence of diabetes in clinical thyrotoxicosis. Obvious or manifest diabetes mellitus would then occur first in those subjects with prediabetes on the verge of developing diabetes mellitus.“” Some speculation is possible concerning the origins of the occasional differences in the blood sugar responses in the various toIerance tests during treatment with thyroid, i.e., the decrease in the hypophosphatemic response
744
DANOWSKI,
BONESSI,
SARVER
AND
MOSES
to glucose, the lessened hypoglycemia at the 1 hour point of the insulin test, the more prolonged hypoglycemia and greater hypophosphatemia after acetohexamide, and the greater hyperglycemic-hypophosphatemic response to epinephrine (table 1 and 3). Such speculation can perhaps be somewhat more fruitful if the blood glucose and the serum inorganic phosphorus changes in tables 1 and 2 are viewed simultaneously.‘“” It must be kept in mind, however, that in spontaneous and induced thyrotoxicosis the serum levels and the urinary excretion of phosphorus may be increased, perhaps independent of any alterations in carbohydrate metabolism.llap” The trend to lessened hypophosphatemia and ultimately to relative hyperphosphatemia during the glucose tolerance test performed in the thyroid treatment period could indicate, among other possibilities, some impairment of processes which pre-empt and segregate inorganic phosphorus, i.e., impairment of phosphorylation and reduced formation of ATP, alone or in combination. The first of these could result from a deficiency of insulin or of effective insulin; in support of the latter is the so-called “uncoupling of oxidative phosphorylation” 12a demonstrable in tissues in the presence of excesses of thyroid hormones. Alternatively, it is possible deficits of hepatic and other glyc!gen stores which are known to develop in thyrotoxicosisti”zb resulted in the deposition of a greater proportion of the glucose load as glycogen, a process which does not pre-empt phosphorus.l:‘:l The shorter duration of the hypoglycemia induced by exogenous insulin during thyroid feeding could reflect a shorter half-life of this hormone under these conditions. Since we would in this case expect as an accompaniment a more prompt return of the serum inorganic phosphorus to the preinsulin level, the failure to observe this either necessitates another explanation for the shortened hypoglycemic response to insulin or requires a mechanism (and none comes to mind) which would serve to prolong the hypophosphatemia. Furthermore, since there is some evidence that the destruction of insulin is increased by thyroid hormone excesses,Ru this would seem to be the preferred explanation for the shortened hypoglycemic effect of exogenous insulin during thyroid hormone excess. The enhancement of this hypoglycemic effect of tolbutamide and of the hypophosphatemic effect of tolbutamide and acetohexamide by thyroid hormone excesses could indicate islet cell hyperfunction or hyperplasia, stemming perhaps from shortened survival of endogenous insulin. The alternative possibility that these drugs potentiate or prolong the action of a given quantity of insulin and that this is enhanced by thyroid hormone excesses finds no support in the results of combined tolbutamide-insulin tolerance tests. However, it is conceivable that during induced thyrotoxicosis the drugs enhance the entry and utilization of glucose in some way other than by inducing a release of insulin. Insofar as the responses to epinephrine during induced thyrotoxicosis are concerned it is logical to expect, in view of the deglycogenating effect of thyroid hormone excesses 6a.b that the usual hyperglycemia and hypophos-
hETABOLISh1
(:AHl3OIIYDHA’lX
AND THYHOID
745
THERAPY
phatemia-induced by this hormone would be decreased. This did not occur. As a matter of fact, just the opposite trends were observed, attaining statistical significance in the 1 hour and 0.5 hour samples, respectively. These findings suggest that at this point in our thyroid feeding studies liver and other glycogen stores were both adequate and readily mobilizable. As a matter of fact, the data are compatible with an increased glycogenolytic response to epinephrine in the presence of thyroid hormone excesses, perhaps as a preliminary to the development of chronic glycogen depletion. REFERENCES la.
R(,g;m,
J. F., and
Wilder,
R. M.:
21.
perthyroidism and diabetes. Arch. Int. hlcd. 65:1116, 1940. Danowski, T. S., Boncssi, J. V., Balaslr, \\!. R., anti Moses, C.: Leucine longation of tolbutamide-induced
poglycemia. 21,. -, -, and amide
and
Metabolism hloses, C.: leucine
hloses,
C.: Acetohexamide
and
SI~d. 115:578, 1964. tl. Hagr*tiorn, H. C., and Jensen, des ~likrol~cstinimung
Fcrricynniti. Biochem. 1:X5:36.1923. 2~. I”isL(a, C. H., and Suhbarow, coiorililc+ric phoru.\. Xl. Alllhrrls,
determination
J, Bioi. Chem. CG.: Beitrsge
phos-
~~i~ilddrusc~nloser, mit Thyroain vori~chantieitcn Katzen. Biochem. Ztschr. 205: 194. 1939. I. .\.,
Tilt. tzffrct tllyroidism
and
Broh-Kahn,
of experimental on carbohydrate
dcrrti Huii. 1935. 3d.
ilyperthyroid Johns Hopkins
~naux
Williams
production
&
4, p. 70. its V’Y-
in
trait&s
par
des
J,
physiol.
gbn. 15:75, 1913. hlirhk). I. A.: The role thv
ticvrlopment
of
dr:,n. J. Pcdiat. %I. Eige:~, N. J.. and fclcts
of tllyroid
I’:{’ drgratiation. 13, 195.5. Ha. 11anowski. a caus: 12:183, 10~. -.
hyperInetab-
animals.
T.
preparations
113.
ct
path.
of the liver ketosis
in
function
on
ins&xl-
Am. J. Physioi. S.:
in
chil-
10:714, 1937. \Villiams, R. H.: Et-
Emotional
of diahrtes 1963.
mcllitus.
180:
stress
il.,
IXabetrs
hlatrer, I;. .\I., and hloses, C.: Cortisone enhancement of peripheral utilization of glucose and of clrlorpropamide. Ann. Acad. SV. 74:988, 1959.
Cook,
I’. B., Nassim,
J, R.,
the effects N\‘rw York and
Col-
lins, J.: The effects of thyrotoxicosis upon the metabolism of calcium. phosphorus, and nitrogen. Quart. J. hlcd. “8:505, 1959.
with thyroxine. Hosp. 56:145,
Rotirigurz, R. R., and MartineL, C.: Preventive action of propylthiouracil 01 rstratiioi on pancreatic diabetes.
Bnitimorc,
Co., 1957. Chapter R.: Hyperthyroidism:
tiryroitiicnnes.
R. H.:
ohm. .I\m. J. Physiol. 117:6, 1936. 2~. Rlc~Eacilc~rn. I).: hlrtabolism of isolated srlrviving tissues from animals rcn-
Adults.
p,Lrimcntal
7a. of
26:127,
Brit. \I. J. 2:1363, 1913. 61~. Parhon, hl.: Sur la tcneur en glycogPnt: tiu foic et d~s muscles chez ies ani-
Y.: ‘I’hc
cl,qica tiberiehender Saiigetierherzcn; ubcsr den Zuckervrrbrauch dcr Herzen S~~lril~ldriiscriloser. sowie normaier lmd
31). \liraky.
Young \Viikins 6a. Farr‘mt,
Ztschr.
66:375, 1925. zur Physiol-
biol.
Danowski, T. S.: IXahetes hlellitus with Emphasis on Children and
B. N.: Zur Biutzuckers
llrittels
dr
1960. 5a.
toihut-
in non-diabetic and diaProc. Sac. Exper. Biol.
argcnt.
R. S., and Berson, S. A.: Immunoassay of endogenous plasma illhuiin in man. J. Clin. Invest. 39: 11.57.
in diabetes
meliitus. lletaholism 11:1141, 1962. 2~. -, S:,rver. hl. E., Bonessi, J. \‘., and amide effects IWic adults.
4a.
SW.
1950. Yaiow,
prohy-
11~556, 1982. Acute tolhut-
effects
Rev.
Hy-
1 lb.
Aub, J. C.. Bnuer. \V., Heath, C., and Ropes. 51.: Stuciirs of calcium and pi~~spi~or~s mrtaholism. III. The ef’-
746
DANOWSKI,
fects
of the thyroid
roid disease. 1929. 12a.
J.
hormone Clin.
and
Invest.
thy-
SARVER
AND
MOSES
Enzyme Chem. Tokyo & Kyoto 2: 297, 1958; Chem. Abstr. 53:16238, 1959.
7:97,
Lehninger, A. L.: Action of thyroxine on mitochondria and oxidative phosphorylation. Proc. Internat. Symposium
BONESSI,
13a.
Nichols,
N.:
The
effect
deposition on liver Clin. Invest. 34:1710,
of
glycogen
phosphorus. 1955.
T. S. Danowski, /M.D., Professor of Medicine, University Pittsburgh School of Medicine, Pittsburgh, Pa.
of
James V. Bonessi, M.D., Fellow in Diabetes and Endocrinology, University of Pittsburgh School of Medicine, Pittsburgh, Pa. Margaret E. Sarver, M.D., Fellow in Diabetes, University of Pittsburgh School of Medicine, Pittsburgh, Pa. Campbell Moses, M.D., Associate Professor of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pa.
J.
Carbohydrate Metabolism Dosage Thyroid (Proloid)
during Large Therapy
BZJT. S. DANOWSKI, J. V. BONESSI, M. E. SANER A battery of tolerance tests which reflect carbohydrate metabolism (glucose, insulin, tolbutamide, acetohexamide and epinephrine) through changes in the levels of the blood sugar and serum inorganic phosphorus were largely unaffected by purified desiccated thyroid (Proloid) therapy which reached dosages of 25 grains per day in successive increments. Tentative interpretations are advanced to explain the few statistically significant changes that were induced by the administration of these large dosages of desiccated thyroid. Judging from blood sugar values the J-hour glucose tolerance test was not altered by these large dosages of desiccated thyroid but such treatment was associated with a more prompt return of the serum inorganic phosphorus to or above the starting levels. The lessened hypophosphatemia during the glucose tolerance test observed in the course of dosage thyroid therapy could reflect decreased use of phosphorus in glycolysis, diminished segregation as a consequence of the formation of ATP, or enhanced deposition of glycogen without phosphorus in depleted tissues, alone or in combination. The equivalent but shortened hypoglycemic response to exogenous irsu-
S
PONTANEOUS creased
of diabetes
now more than 2 decades
in man
mellitus.
old hut based
C. MOSES
lin observed during thyroid feeding was not accompanied by a more prompt return of serum inorganic phosphorus levels to the preinsulin values. Evidence from other studies that the biologic halflife of insulin is shortened by thyroid hormone excesses prompts the suggestion that this is responsible for the shortening of the hypoglycemia, but this does not explain the failure to observe a comparable shortening of the hypophosphatemic response to insulin. Trends to increased hypoglycemic and hypophosphatemic effects of tolbutamide and acetohexamide during thyroid hormone excesses could reflect islet cell hyperfunction or hyperplasia induced, perprior thyroid feeding haps, during secondary to a shortening of the biologic half-life of insulin. The usual hyperglycemic-hypophosphatemic responses to exogenous epinephrine were enhanced by large dosages of desiccated thyroid, suggesting that despite such therapy hepatic and other glycogen stores were intact and readily mobilizable. It ma} be that the first response to thyroid hormone excesses is an enhancement of glycogenolysis and that glycogen depletion is a subsequent event.
THYROTOXICOSIS
prevalence
AND
is associated
The data of Regan
on 1,883 patients
with
an in-
and Wilde+
with hyperthyroid-
740
DANOWSKI, BONESSI, SARVER AND MOSES
ism indicated the prevalence of diabetes mellitus in hyperthyroidism to be 3.2 per cent. This composite figure was derived from a 1.7 per cent frequency in patients with exophthalmic toxic goiter and a 5.6 per cent frequency in those with toxic thyroid adenomata. Opportunities to test carbohydrate metabolism prior to the onset of spontaneous thyrotoxicosis are limited. We have therefore undertaken by means of various tolerance tests to quantitate carbohydrate metabolism in a group of healthy adult prisoners prior to and while receiving a purified preparation of desiccated thyroid (Proloid), 25 grains per day. MATERIALS Blood
sugar
and serum
inorganic
AND METHODS
phosphorus
responses
to oral
glucose
and to intra-
venous insulin, tolbutamide, acetohexamide and epinephrine were determined in 10 healthy young adult prisoners between the ages of 22 and 51 years. In each case the test was initiated between 6:30 and 7:00 a.m. following an overnight fast. Except during the epinephrine tolerance the subjects sat quietly without smoking. The epinephrine test, however,
was performed
The glucose
with the men lying on a bed.
was ingested
per Kg. of body of body weight,
weight.
as a 56 per cent solution in water
In the insulin tolerance
was injected
intravenously
test regular
at a dosage
of 1.75
insulin, 6.1
unit per
at zero time immediately
0.9 per cent saline solution for ease of measurement.
A standard
after
dilution
Gm. Kg. with
dose of sodium tolbut-
amide, 1.0 Gm., in 20 ml. of distilled water, was infused intravenously during a 2 to 3 minute intervalsarb The same dosage and procedure were followed with acetohexamide,sc save that a 2.5 per cent solution in phosphate
buffer
(inorganic
phosphorus
concentration
of 79 mg. per cent) was used. The epinephrine tolerance test was based upon the subcutaneous injection of 0.01 unit of a 1:lOOO commercial solution of epinephrine hydrochloride per Kg. of body weight administered in 3 equal parts at zero, 10 and 20 minutes. Samples
of venous
serum inorganic
blood
phosphorus
lowing the administration
were
withdrawn
(Fiske-Subbarow)
for
blood
sugar
(Hagedorn-Jensen)
analysess”se prior to and at intervals
and fol-
of the test material. RESULTS
A. Glucose
Tolerance
Tests
In the oral glucose tolerance test the ingestion of 1.75 Gm. of the sugar per Kg. of body weight produced comparable hyperglycemia prior to and during the ninth week of therapy with desiccated thyroid in increasing dosages which had reached 25 grains per day at the time of tolerance test. In neither test was there any delay in the disposal of the glucose load, judging from the peak and the 2-hour blood sugar values. In each group a distinct hypoglycemic tail was evident at or beyond the second hour (table 1) . Although the mean decreases in inorganic phosphorus during the glucose tolerance (table 2) were less in the first 3 hours of the test conducted during the ingestion of 25 grains of desiccated thyroid, the differences between these decrements and those recorded in the control period were not statistically significant. However, in the fourth and fifth hours of the glucose tolerance test conducted during the treatment period the serum inorganic phosphorus rose distinctly above the starting level, while during the same segment of
CARBOHYDRATE
XIETABOLIS,M
Table l.-Blood
AND
THYROID
741
THERAPY
Sugar Values (mg. %) during Various Prior fo and during Thyroid Therapy
Tolerance
Tests
__.~
___~~_.
Control Mean F S.D.
Oral
o-o.5 hr.
glwnst~:
39.4 i- 29.4 6.6 t 16.7 -6.2 t 15.9
O-l.0 hr. O-2.0 hr.
-11.8 -12.2 -8.2
?I 19.0 -c 7..5 fr 6.5
10 10 10 4
-.53.7 -31.2 -19.6 -7.2
t t + -ir
H 8 8 8 8 8
-26.6 -375 -28.0 -IS,.5 -13.9
O-3.0 hr. o-4.0 hr. O-5.0 hr. Inwlin:
O-0.5 hr. O-1 .O hr. O-l.rj hr. O-2.0 hr.
Tolhutamidc:
O-15 O-30 O-45 O-60 O-90
min. min. min. min. min.
O-120
Thyroid: Mean
min.
-6.4
i- 14.5
-4.2 -10.0
i- 18.3 -c 15.2
15.2 10.1 17.7 6.7
A9.5 -20.0 -10.6
k t t
t
10.1
t t t t
8.1 13.6 3.x 10.5
-30.5 -31.2 -33.2 -23.0 -15.0 -19.1
-t 18.1 I!Z 8.9 t 11.8 f 12.6 -t- 12.8 i 11.0”
-0.8
k 4.1
10.3 13.1° Il.6
-t 9.1
- “7.1
i 7.3
-:3.3.0
-c 16.l)
-31.4 -32.9 -24.2 -1o.F;
i +_ t i
-%3.2 -:34.6
i l-1,.3 & 10.3
-16.9
i- 10.3
--33.1 -21.6 -23.Fi
-4 S.5 t Il.4 i- 8.4
x 8
O-4.5 min. O-60 min. O-90 min. O-1 20 min.
8 8 8 8
n-o.5 hr. O-1.0 hr.
7 7
31 .o : 9.7 27.4 ri 9.6
O-l.5 hr. O-2.0 hr.
7 7
18.3 -c 10.9 lFi.0 IL 17.0
min.
36.4 -+ 21.3 3.6 +- 29.5 2.3 -t 13.0 -6.6
O-30 min.
O-l.5
25 grains/d t S.D.
7.3 10.7 8.6 .5,6
“5.0 1 13,s 36.1 -+ 10.8” 22.6 k 16.0 10.3 -c 9.2
*Paired I-tests: p < .I%, the control Thus
tolerance
the phosphorus
at 5 hours the mean
per cent.
The
less than
0.01).
H. Insulin Even
difference
Tolerance though
duration
by the ingestion
of the response from
parison
of the differences
The
the blood
decreases
insulin
ment phases.
these
2 means
sugar
of large
levels
between
tests
The slight
response
was distinctly
in serum
tolerance
in the 2 tests were
to its zero value.
fO.91
and
is statistically
-0.01
mg.
significant
(11
Tests
judging
the
between
the hypoglycemic
was not affected
had not yet returned
changes
at 1 hour
during
present
point
thyroid,
treatment
were the
at that
com-
point).
of equal
control
the
period,
(11 less than 0.05 upon values
phosphorus
conducted
at the 30 minute
of desiccated
less in the thyroid
the mean
inorganic
differences
to insulin dosages
and
were not statisticallv
magnitude thyroid
iI1
treat-
significant.
742
DANOWSKI,
Table B.-Serum .~
BONESSI,
SARVJZR AND
MOSES
Znorganic Phosphorus Changes during Various Tolerance Tests Prior to and during Thyroid Therapy Subjects (if)
Control Mean 2 S.D.
Thyroid: 25 grains/d Mean Y? S.D.
Oral glucose:
O-O.5 hr. O-l .O hr. O-2.0 hr. O-3.0 hr. 04.0 hr. O-5.0 hr.
4 5 4 5 5 5
-0.69 -0.96 -1.16 -0.63 -0.24 -0.01
+ t f + -t *
0.5 0.7 0.4 0.4 0.5 0.4
-0.47 -0.56 -0.73 -0.29 0.45 0.91
ir t * 3: * -t
0.2 0.1 0.3 0.4 0.4 O.lf
Insulin:
O-O.5 hr. O-l .O hr. O-l.5 hr. O-2.0 hr.
10 10 10 3
-1.60 -1.27 -0.86 -0.40
X!X0.4 k 0.5 t 0.5 * 0.2
-1.59 -1.20 ---0.71 --0.67
-c f t -t
0.3 0.5 0.5 0.5
Tolbutamide:
O-15 min. O-30 min. O-45 min. O-60 min. O-90 min. O-120 min.
8 8 8 8 8 8
-0.33 -0.68 -0.87 -0.71 -0.63 -0.62
-+ + -c * t f
--0.75 -1.15 -1.26 - 1.39 -1.34 -1.24
2 -+ .t c t rt
0.3 0.5 0.4 0.6* 0.6* 0.7
Acetohexamide:
O-15 min. O-30 min. O-45 min. O-60 min. O-90 min. O-120 min.
8 8 8 8 8 8
-0.03 & 0.4 -0.47 zk 0.5 -0.84 t 0.4 -0.94 -t 0.4 -0.76 + 0.4 -0.67 f 0.4
-0.45 k 0.6 -1.23 + 0.3’ -1.38 t 0.6 -1.49 k 0.6 -1.45 -t 0.7’ -1.19 Xk 0.v
Epinephrine:
O-O.5 O-1.0 O-l.5 O-2.0
7 7 7 7
-0.48 -0.63 -0.36 -0.55
-1.42 -1.05 -0.61 0.33
“Paired tP
<
t-tests:
hr. hr. hr. hr.
-c i k 2
0.4 0.4 0.4 0.4 0.4 0.4
0.1 0.2 0.6 0.1
+ & + t
0.5” 0.4 0.3 0.4
p < .05.
.Ol.
C. Tolhutamide
nnd Acetohexamide
Tolerance
Tests
There is a suggestion that during thyroid feeding these 2 drugs were more effective in producing hypoglycemia, but this trend, insofar as the blood sugar responses are concerned, reached statistical significance only at the 2-hour point of the tolbutamide tests. Further support for this view can be adduced, however, if the serum inorganic phosphorus changes are taken into account. These indicate that with both drugs thyroid feeding enhanced the usual hypophosphatemia at several points during the tolerance test (table 2). D. Epinephrine
Tolerance
Test
The daily ingestion of 25 grains of desiccated thyroid was associated with but two changes in the response to subcutaneous epinephrine: the hyperglycemic response at 1 hour was enhanced and the hypophosphatemia at the half-hour point was greater.
CARBOHYDRATEMETABOLISM AND THYROIDTHERAPY
743
DISCUSSION The absence of a striking effect of these large amounts of desiccated thyroid upon various indices of carbohydrate metabolism may be related to the dosage, the duration of therapy, the characteristics of the thyroid hormone preparation or the nonsusceptibility of the subjects. With regard to the first two of these obviously spontaneouus thyrotoxicosis may be more severe and of much longer duration than was the hyperthyroidism-induced in this study. These factors could account for our failure to observe any diabetogenic action of the purified desiccated thyroid preparation. It is unlikely that any special quality of this purified and standardized preparation of desiccated thyroid was responsible for the absence of a diabetogenie effect, though this has not been tested. Insofar as the susceptibility of subjects of these studies is concerned, it is, of course, true that diabetes mellitus is less frequent in youth and that the highest coincidence of thyrotoxisis and diabetes mellitns occurs in patients older than the subjects used in this study. The data presented do suggest, however, that large dosages of desiccated thyroid are not immediately diabetogenic. As a matter of fact in vitro studies indicate that thyroid hormone facilitates the disposal of glucose.““-fI Hence the occurrence of diabetes mellitus in a previously nondiabetic subject and the aggravation of existing diabetes mellitus by excesses of thyroid hormone must be sought in other mechanismsSa It is possible, for example. that the increased intake of food which characterizes spontaneous thyrotoxicosis ultimately exhausts the insulinogenic reserves of the pancreas with or without affecting the levels of effective insulin. Also, the increased absorption of foodstuffs, and of sugar in particular, from the gut which characterizes thyrotoxicosis might raise the peak levels of blood sugar and thereby make further demands upon insulin secretion. In a patient with known diabetes mellitus the increased reabsorption of filtered glucose by the kidney could have a similar effect. Furthermore the marked decrease in hepatic glycogen produced by thyroid hormone excesse+J could be expected to decrease carbohvdrate tolerance, since these circumstances evoke a mobilization of depot fat and ketone body production.i8 Again in established diabetes mellitus one might anticipate that such deglycogenation would render more difficult the regulation of carbohydrate metabolism, induce shocking, and thereby modify the insulin requirement. Finally, it is possible that thyroid hormone accelerates the destruction of insulin.hX One must conclude therefore that it is a sum total of these and other unidentified diabetogenic factors evoked secondary to thyroid hormone excesses that is responsibIe for the higher prevalence of diabetes in clinical thyrotoxicosis. Obvious or manifest diabetes mellitus would then occur first in those subjects with prediabetes on the verge of developing diabetes mellitus.“” Some speculation is possible concerning the origins of the occasional differences in the blood sugar responses in the various toIerance tests during treatment with thyroid, i.e., the decrease in the hypophosphatemic response
744
DANOWSKI,
BONESSI,
SARVER
AND
MOSES
to glucose, the lessened hypoglycemia at the 1 hour point of the insulin test, the more prolonged hypoglycemia and greater hypophosphatemia after acetohexamide, and the greater hyperglycemic-hypophosphatemic response to epinephrine (table 1 and 3). Such speculation can perhaps be somewhat more fruitful if the blood glucose and the serum inorganic phosphorus changes in tables 1 and 2 are viewed simultaneously.‘“” It must be kept in mind, however, that in spontaneous and induced thyrotoxicosis the serum levels and the urinary excretion of phosphorus may be increased, perhaps independent of any alterations in carbohydrate metabolism.llap” The trend to lessened hypophosphatemia and ultimately to relative hyperphosphatemia during the glucose tolerance test performed in the thyroid treatment period could indicate, among other possibilities, some impairment of processes which pre-empt and segregate inorganic phosphorus, i.e., impairment of phosphorylation and reduced formation of ATP, alone or in combination. The first of these could result from a deficiency of insulin or of effective insulin; in support of the latter is the so-called “uncoupling of oxidative phosphorylation” 12a demonstrable in tissues in the presence of excesses of thyroid hormones. Alternatively, it is possible deficits of hepatic and other glyc!gen stores which are known to develop in thyrotoxicosisti”zb resulted in the deposition of a greater proportion of the glucose load as glycogen, a process which does not pre-empt phosphorus.l:‘:l The shorter duration of the hypoglycemia induced by exogenous insulin during thyroid feeding could reflect a shorter half-life of this hormone under these conditions. Since we would in this case expect as an accompaniment a more prompt return of the serum inorganic phosphorus to the preinsulin level, the failure to observe this either necessitates another explanation for the shortened hypoglycemic response to insulin or requires a mechanism (and none comes to mind) which would serve to prolong the hypophosphatemia. Furthermore, since there is some evidence that the destruction of insulin is increased by thyroid hormone excesses,Ru this would seem to be the preferred explanation for the shortened hypoglycemic effect of exogenous insulin during thyroid hormone excess. The enhancement of this hypoglycemic effect of tolbutamide and of the hypophosphatemic effect of tolbutamide and acetohexamide by thyroid hormone excesses could indicate islet cell hyperfunction or hyperplasia, stemming perhaps from shortened survival of endogenous insulin. The alternative possibility that these drugs potentiate or prolong the action of a given quantity of insulin and that this is enhanced by thyroid hormone excesses finds no support in the results of combined tolbutamide-insulin tolerance tests. However, it is conceivable that during induced thyrotoxicosis the drugs enhance the entry and utilization of glucose in some way other than by inducing a release of insulin. Insofar as the responses to epinephrine during induced thyrotoxicosis are concerned it is logical to expect, in view of the deglycogenating effect of thyroid hormone excesses 6a.b that the usual hyperglycemia and hypophos-
hETABOLISh1
(:AHl3OIIYDHA’lX
AND THYHOID
745
THERAPY
phatemia-induced by this hormone would be decreased. This did not occur. As a matter of fact, just the opposite trends were observed, attaining statistical significance in the 1 hour and 0.5 hour samples, respectively. These findings suggest that at this point in our thyroid feeding studies liver and other glycogen stores were both adequate and readily mobilizable. As a matter of fact, the data are compatible with an increased glycogenolytic response to epinephrine in the presence of thyroid hormone excesses, perhaps as a preliminary to the development of chronic glycogen depletion. REFERENCES la.
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T. S. Danowski, /M.D., Professor of Medicine, University Pittsburgh School of Medicine, Pittsburgh, Pa.
of
James V. Bonessi, M.D., Fellow in Diabetes and Endocrinology, University of Pittsburgh School of Medicine, Pittsburgh, Pa. Margaret E. Sarver, M.D., Fellow in Diabetes, University of Pittsburgh School of Medicine, Pittsburgh, Pa. Campbell Moses, M.D., Associate Professor of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pa.
J.