EFFECT OF INSULIN HYPOGLYCEMIA ON ALIMENTARY

HYPERGLYCEMIA*
BY MICHAEL SOMOGYI
(From the Laboratory of the Jewish Hospital of St. Louis, St. Louis, Missouri)

(Received for publication, June 16, 1951)

Insulin action is generally associated with an acceleration of glucose

assimilation. If, for instance, a healthy person in the postabsorptive state
is given glucose and simultaneously receives a small intravenous dose
(from 3 to 5 units) of insulin, the resulting blood sugar time curve (glucose
tolerance curve) is much flatter than one obtained upon feeding the same
amount of glucose but without the injection of insulin. Another notable
change produced by insulin action after glucose feeding occurs in the

Downloaded from http://www.jbc.org/ by guest on September 22, 2018

arteriovenous differences of blood sugar: injected insulin increases the ar-
teriovenous differences, a change which reflects an increase in the rate of
peripheral (extrahepatic) glucose assimilation.
In the present report it will be shown that an entirely different picture
unfolds itself when the injection of insulin precedes the administration of
glucose by from 40 to 50 minutes, so that hypoglycemia can develop during
this interval. Under this condition alimentary hyperglycemia rises to
much higher levels and the arteriovenous differences become smaller than
without insulin injection; that is, insulin injection entails a depression in
the rate of glucose assimilation and causes deterioration of the glucose
tolerance. Hyperglycemia can rise under this conditian to such high levels
as to produce glycosuria, a transient state of diabetes in healthy men.
In diabetic persons this process manifests itself in pronounced exacerbation
of the hyperglycemia and glycosuria, and often gives rise to ketonuria.
The experiments which revealed this paradoxical insulin effect were
prompted by previous observations which demonstrated the fact that
insulin hypoglycemia excites the adrenal-pituitary system to an increased
secretion of hormones (l-4) which elevate the glycemic level and thereby
inhibit, and even may completely counteract, insulin action (4, 5). To
determine to what extent hypoglycemia can interfere with the action of
insulin upon alimentary hyperglycemia, we carried out experiments in
which insulin was injected in order to produce hypoglycemia and mobilize
the insulin-antagonistic system a short time before the administration of
glucose. The results were compared with those obtained when an iden-
tical dose of insulin was injected simultaneously with glucose feeding, as
well as with the effect of glucose feeding alone.
* This work was aided by the David May-Florence G. May Fund.
859
860 INSULIN HYPdGLYCEMIA

Procedure
From previous studies it was known that the hypoglycemia must be
maintained about as low as 60 mg. per cent in order to excite adrenal-
pituitary activity to a substantial extent, so that its insulin-antagonistic
effects would be unequivocally manifested in changes of the glycemic levels
and arteriovenous differences (4). The minimum, or near minimum, in-
sulin dose was used to produce the required degree of hypoglycemia; this
was important, since large, grossly unphysiological doses, such as are fre-
quently employed in experimental studies, may obliterate the action of
moderate amounts of insulin-antagonistic factors. We have known that
from 3 to 6 units, injected intravenously, suffice to produce the desired
degree of hypoglycemia in healthy young men weighing from 65 to 80

Downloaded from http://www.jbc.org/ by guest on September 22, 2018

kilos (2). In these experiments 4, occasionally 5, units of insulin were
employed. Finally, we had to choose the proper time interval between
insulin injection and glucose feeding. According to previous work (2, 4),
4 or 5 units of insulin produce the lowest glycemic level within 20 or 30
minutes after intravenous injection. At this point the blood sugar rises
sharply and in about the next 60 minutes returns to near the initial fasting
level. The course of the blood sugar curve represents at any given instant
the balance between the action of insulin in one direction and the action
of its antagonists in the opposite. Thus it is evident that at the start of
the upswing of the curve the balance tips in favor of the blood sugar-
raising factors, and that their action becomes actually greater than insulin
action, despite the fact that the greater part of the injected insulin is still
present in active form. The rising leg of the curve is, as a rule, steepest
between the 30th and 40th minute after injection, indicating that the
action of the insulin antagonists at that time exceeds the action of the
available insulin. In the light of this information, we have employed in
these experiments an interval of from 40 to 50 minutes between the in-
jection of insulin and the oral administration of glucose.
Healthy young men served as subjects, as best suited for a study of
this kind. Blood sugar was determined in capillary and venous blood
samples drawn simultaneously by procedures previously described (5),
which permit the estimation of arteriovenous differences with sufficient
accuracy.
E$ect of Insulin Hypoglycemia on Glucose Tolerance of Healthy Men
Seven subjects were used in these experiments, undergoing two glucose
tolerance tests within 1 week, during which they lived on a fairly uniform
diet. In the first test they were given 50, 75, or 100 gm. of glucose; in
the second test insulin was injected from 30 to 50 minutes before the ad-
ministration of an identical amount of glucose. Blood sugar was deter-
 M. SOMOGYI 861

mined in venous and arterial (capillary) blood samples, in most instances

at 30 minute intervals.
An example of the results is graphically presented in Fig. 1. The curves
represent two glucose tolerance tests (venous blood sugar) on a young man
(G. C.), after oral administration of 100 gm. of glucose. The first test,
a conventional tolerance test, yielded a typically normal curve (Curve I),

Downloaded from http://www.jbc.org/ by guest on September 22, 2018

FIG. 1 FIG. 2
FIG. 1. Glucose tolerance curves showing a paradoxical action of insulin in a
healthy man. Curve I was obtained after the oral administration of 100 gm. of
glucose. Curve II is the result of a second test, in which 4 units of insulin were
injected intravenously 45 minutes before glucose feeding. The intervening hypo-
glycemic interval caused deterioration of glucose tolerance.
FIG. 2. Glucose tolerance curves showing normal insulin action in a healthy man.
Curve I is the result of a conventional tolerance test after ingestion of 50 gm. of
glucose. Curve II represents a test in which 4 units of insulin were injected simul-
taneously with the ingestion of 50 gm. of glucose. Insulin virtually suppressed
alimentary hyperglycemia.

characterized, first, by a hyperglycemic peak lower than 150 mg. per cent
and, second, by the decline of the blood sugar during the second half hour
period. In the second test 4 units of insulin were injected intravenously,
45 minutes before ingestion of the glucose. The resulting tolerance curve
(Curve II) was vastly different. The initial blood sugar at the moment
of glucose feeding showed a near recovery from the insulin hypoglycemia,
but it was still somewhat lower than the normal fasting level. Regardless
of this lower initial level, however, alimentary hyperglycemia had risen
much bigher than without the injection of insulin: 204 mg. per cent in the
venous (229 mg. per cent in the arterial) blood. As further signs of greatly
362 INSULIN HYPOGLYCEMIA

impaired glucose tolerance, the decline started only during the 2nd hour
after glucose feeding, instead of the half hour interval, and considerable
hyperglycemia still persisted at the end of the 2nd hour. There was also
glycosuria; the urine excreted during the 2 hours contained 0.5 per cent
glucose. This tolerance test presented an unequivocal picture of a mild
state of diabetes.
It is obvious from the course of Curve II that the action of the insulin-
antagonistic (blood sugar-raising) hormones greatly outstripped the com-
bined action of the injected plus the endogenous insulin, which undoubtedly
was secreted at an increased rate under the stimulus of the protracted
hyperglycemic period. In the course of 1 hour following glucose feeding,
the overactivity of the adrenal-pituitary system subsided and the excess

Downloaded from http://www.jbc.org/ by guest on September 22, 2018

of the insulin-antagonistic hormones which they put into circulation was,
as we have shown (4), to a great extent dissipated. In consequence, the
increased insulin supply elicited by the hyperglycemia could act without
inhibition, as reflected in a rather sharp fall of the glycemic level.
A diametrically opposite effect is obtained when insulin is injected si-
multaneously with glucose feeding (6), a condition permitting the insulin
to act without the interference of hypoglycemia. Fig. 2 illustrates the
latter response. As may be seen, in this instance the injected insulin was
sufficient to suppress alimentary hyperglycemia almost completely.
The fundamental significance .of this difference between the action of
identical doses of insulin is further illustrated by an experiment in which
the subject (L. S.) had undergone three tests, as shown in Fig. 3. Follow-
ing the administration of 100 gm. of glucose, the glucose tolerance of the
subject was normal (Curve I). .The effect of 5 units of insulin injected
simultaneously with the ingestion of glucose is shown in Curve II. As
may be noted, the insulin completely suppressed alimentary hyperglycemia
and even produced hypoglycemia, evidently because the intestinal absorp-
tion rate of glucose could not cope with the highly increased rate of assimi-
lation. But when the injection of 5 units of insulin preceded the ingestion
of glucose by 40 minutes, the blood sugar-raising factors, mobilized by
the intervening hypoglycemic interval, caused a substantial deterioration
of the glucose tolerance (Curve III).
As has been pointed out in our previous papers (2, 4), changes in the
glycemic level are interpreted as the expression of ‘dynamic, shifting bal-
ances between the action of insulin and its antagonists. Thus Curve II
in Fig. 1 and Curve III in Fig. 3 reflect a condition in which the balance
was shifted in favor of the insulin-antagonistic hormones. Fig. 4 illus-
trates the sensitivity of this balance. In a previous study (4) we showed
that by the time the blood sugar returns to or near its normal postab-
sorptive level after an injection of insulin the insulin-antagonistic response,
 M. SOMOOYI 363

elicited by hypoglycemia, has almost subsided. In the experiment pre-

sented in Fig. 4 glucose feeding was delayed by 60, instead of 40, min-
utes after the injection of 4 units of insulin. During this prolonged
interval the blood sugar had returned to its normal level, allowing the
insulin-antagonistic forces to weaken. As a consequence, as shown in

Downloaded from http://www.jbc.org/ by guest on September 22, 2018

FIG. 3 FIG. 4
FIG. 3. Glucose tolerance curves obtained on a healthy man after oral administra-
tion of 100 gm. of glucose in each instance. Curve I is the result of the conventional
test. Curve II shows increased glucose tolerance when 5 units were injected simul-
taneously with glucose feeding. Curve III shows deterioration of glucose tolerance
when the same dose of insulin was injected 40 minutes before glucose feeding and
thus was allowed to produce hypoglycemia.
FIG. 4. Glucose tolerance curves showing the rapid dynamic shift between insulin
and its antagonists. Curve I represents a conventional tolerance test with 100 gm.
of, glucose. Curve II, 4 units of insulin injected 60 minutes before glucose feeding.
During this prolonged interval the blood sugar returned to its normal level, allowing
much of the insulin-antagonistic activity to subside; thus little diabetogenic action
was exerted.

Curve II, alimentary hyperglycemia in this test did not rise higher than in
the conventional tolerance test represented by Curve I. That portion of
the injected insulin which was still circulating in active form at the mo-
ment of glucose feeding evidently sufficed virtually to cancel the excessof
insulin-antagonistic factors which were still present. Equally instructive
were the results of other experiments in which the interval between insulin
injection and glucose feeding was shortened to 20 or 30 minutes. Under
this condition the diabetogenic effect of hypoglycemia could be detected
only on close analysis of the results. It was slight because the short hypo-
864 INSULIN HYPOGLYCEMIA

glycemic interval did not allow enough time for the excitation and increased
secretory activity of the adrenal-pituitary system, so that its influence
TABLE I
E$ect of Short Hypoglycemic Interval before Glucose Feeding

Blood sugar’ Rise above initial level

I
Time after glucose
feeding (SO pm.)
4 units intravenously
No insulin 30 min. before glucose No insulin 4 units insulin

hrs. mg. ger cent mg. per cent mg. per cent ntg. per cent
0 90 42
0.5 203 166 113 124
1 170 167 80 125

Downloaded from http://www.jbc.org/ by guest on September 22, 2018

2 63 83 -27 +41

* Determined in capillary (finger) blood.

TABLE II
Showing Impairment of Glucose Tolerance As Sequel to Insulin Hypoglycemia

Blood sugar’ Rise above initial level

Subject Glucose dose Time after -
lucose feedin! :-
No insulin With insulint No insulin 4I units insulin
_-
km. hrs. .I-mg. ger cent mg. ger cent mg. per cent mg. ger cert
G. I. 100 0 85 74
0.5 120 154 35 80
1 91 179 6 105
2 111 125 26 51
3 96 105 11 31
M. B. 50 0 78 62
0.5 90 157 12 95
1 110 174 32 112
1.5 96 96 18 34
2 71 70 -7 +8
M. S. 75 0 97 65
0.5 161 170 64 105
1 192 217 95 152
1.5 156 227 59 162
2 127 199 30 134
3 68 100 1 35
M. SC. 100 0 93 64
0.5 170 140 77 76
1 184 204 91 140
1.5 138 162 45 98
2 101 127 8 63

* Determined in capillary (finger) blood.

t Each of these subjects was given 4 units of insulin intravenously 40 minutes
before glucose feeding.
 M. SOMOGYI 865

could be nearly balanced by the injected insulin. This is illustrated by

the data of Table I, from which it may be seen that the hyperglycemic
peak after glucose feeding was lower after insulin hypoglycemia than in
the plain tolerance test. Yet the effect of the insulin-antagonistic fac-
tors, elicited by hypoglycemia, is still manifest in the greater span between
the initial glycemic level and the hyperglycemic peak, and is even more
clearly in evidence at the 1 and 2 hour intervals after glucose feeding.
It is obvious that, owing to these highly dynamic and delicate shifts in
the quantitative relationship between the active insulin supply and its
opposing endocrine factors, the diabetogenic sequel of insulin hypogly-
cemia may easily elude observation. Only awareness of this fact makes
it possible to demonstrate this reaction unequivocally, as in the experi-

Downloaded from http://www.jbc.org/ by guest on September 22, 2018

ments presented in Figs. 1 and 3. In view of the practical significance
of this phenomenon in its bearing on insulin therapy, in Table II we have
recorded four more illustrative experiments. It may be noted that in
every one of these subjects insulin hypoglycemia caused a distinct impair-
ment of glucose tolerance, as reflected in the higher hyperglycemic peaks
and in the pronounced rise of the peaks above the initial glycemic levels.
The foregoing experiments, then, demonstrate the fact that injection of
insulin can exert two diametrically opposite effects on glucose assimilation.
If the insulin is injected simultaneously with the administration of glucose,
the rate of assimilation is substantially enhanced. This is in line with
the generally recognized action of insulin. If, however, insulin is injected
some time before glucose feeding, and thus is allowed to produce a hypo-
glycemic interval, it seriously depressesthe rate of glucose assimilation.
It impairs glucose tolerance because hypoglycemia excites the adrenal-
pituitary system to increased activity, enhancing the secretion of hormones,
which act in a direction diametrically,opposite to insulin action.

E$ect of Insulin Hypoglycemia on Glucose Tolerance of Diabetic Persons

The diabetogenic effect of insulin hypoglycemia prevails in the diabetie
just as in the healthy person. But while the physiological reaction in the
two is qualitatively the same, it is of a much higher order of magnitude in
the diabetic. This great quantitative difference makes the phenomenon
more readily observable in diabetic than in normal persons.
That glucose tolerance is more severely impaired by hypoglycemia in
the diabetic than in the normal person is evidently due to the fact that
in the diabetic state insulin action, not necessarily the supply (2), is already
deficient, relative to the action of the blood sugar-raising adrenal-pituitary
factors; hence, when the latter are excited by hypoglycemia, their increased
activity proceeds against less resistance, with a greater momentum than
in the healthy person.
866 INSULIN HYPOGLYCEMIA

Discussion of the bearing of this fact on the practice of insulin therapy

is outside the scope of this report. We have dealt with this aspect of the
problem in preliminary reports elsewhere (7-9). Here we wish to present
only a single example of experiments on diabetic persons, in order to char-
acterize their response to insulin hypoglycemia. The subject in this ex-
periment was a 55 year-old man, diabetic for 6 years. His treatment was
based on the therapeutic effect of a dietary regimen consisting of 100 to
120 gm. of protein, 280 to 300 gm. of carbohydrate, and 60 to 80 gm. of
fat (a lipotropic diet). On this regimen his condition improved consist-
ently; he conducted a perfectly normal healthy life (he is a manual worker)
and had been completely aglycosuric during the 11, months directly pre-
ceding this experiment.

Downloaded from http://www.jbc.org/ by guest on September 22, 2018

In this experiment we followed the same procedure as in those on healthy
subjects. The first test was a conventional glucose tolerance test, with
oral administration of 100 gm. of glucose.. 1 week after this, 3 units of
insulin were injected intravenously, simultaneously with glucose feeding.
In a third similar test, 4 days after the second, the insulin dose was in-
creased to 5 units. In a fourth test insulin hypoglycemia preceded glucose
feeding. The results of the first three tests are given in Fig. 5. Curve I,
the glucose tolerance test, reflects a full-fledged diabetic state, with a ve-
nous hyperglycemic peak of 416 mg. per cent 2 hours after glucose feeding.
Curve II shows the influence of the small dose of 3 units of insulin; it is
most conspicuous during the 1st and 2nd hours after the ingestion of glu-
cose, at the end of which intervals the sugar in the venous blood had risen
to only 153 and 228 mg. per cent, as against 337 and 416 mg. per cent,
respectively, in the test without insulin.
The remarkable efficiency of insulin action is emphatically shown by
the fact that 3 units accelerated the, rate of assimilation so vigorously that
the rate of intestinal absorption could not cope with it, with the conse-
quence that the blood sugar was depressed below the fasting level and was
held there for at least 1 hour after glucose feeding. Only when the in-
sulin action had been gradually dissipated could the rate of intestinal ab-
sorption outdistance the rate of assimilation and lead to alimentary hy-
perglycemia.
Test 3 (Curve III) again points to the great efficacy of insulin action.
Compare Curves II and III and note how potently an increment of the
insulin supply by a mere 2 units has accelerated glucose assimilation in a
diabetic man, weighing 62 kilos. While 3 units kept blood sugar 1 and 2
hours after glucose feeding at the levels of 134 and 153 mg. per cent, re-
spectively, the addition of 2 units further depressed the corresponding
glycemic levels to 95 and 94 mg. per cent. Such response to insulin is not
exceptional; it was of the same order in all of our experiments on diabetic
 M. SOMOGYI 867

subjects who had not been under the influence of endocrine and dietary
insulin-antagonistic factors.
In Test 4 the patient was injected with 7 units of insulin and was fed
100 gm. of glucose 75 minutes after the injection. At this time the blood
sugar had begun to rise from its low hypoglycemic level, indicating that
the effect of the adrenal-pituitary hormones had outstripped the action of
the injected insulin, of which about from 4 to 5 units were still in an

Downloaded from http://www.jbc.org/ by guest on September 22, 2018

TIME -HOURS-AfTER
FIG. 5 FIG. 6
FIG. 5. Glucosetolerancecurvesshowingnormalinsulin action in a diabetic man.
In eachtest 100gm. of glucosewere given orally. Curve I was obtainedin a con-
ventional tolerancetest, Curve II with 3 units, and Curve III with 5 units of intra-
venousinsulin injected simultaneouslywith glucosefeeding.
FIG. 6. Glucosetolerancetests in a diabetic man showingthe diabetogeniceffect
of insulinhypoglycemia. In A, Curve I is the result of a test after the oral adminis-
tration of 100gm. of glucose;Curve II representsa test in which 7 units of insulin
were injected 75 minutes before glucosefeeding. B representsthe sameexperi-
ment in different terms (seethe text).
active form when the glucose was ingested. In Fig. 6, A, Curve I repre-
sents the conventional glucose tolerance test, while Curve II shows the
effect of insulin hypoglycemia that preceded glucose feeding. It may be
noted that in the latter instance the hyperglycemic peak was distinctly
higher than in the test without insulin injection, although the initial blood
sugar level was much lower. In addition, hyperglycemia was more sus-
tained and more persistent in the test after insulin injection than in the
plain tolerance test. This difference can be better visualized in Fig. 6, B,
where the rise of the blood sugar above the fasting level is presented in-
stead of the actual glycemic levels. These curves show that in the con-
868 INSULIN HYPOGLYCEMIA

ventional tolerance test the blood sugar was 200 mg. per cent above the
fasting level at the end of 3 hours, whereas under the influence of insulin
hypoglycemia it rose by 370 mg. per cent above the base point.

TABLE III
Showing Deterioration of Glucose Tolerance and Depression of Peripheral Glucose
Assimilation As Aftermath of Insulin Hypoglycemia

100 grh. glucose by mouth, no insulin

Downloaded from http://www.jbc.org/ by guest on September 22, 2018

min. w. mc. mg.per cent
1 0 180.6 179.5 1.1
30 261.1 253.8 7.3
60 350.2 336.7 13.5
120 443.3 416.3 27.0
180 405.5 380.2 25.3

100 gm. glucose by mouth, 3 units insulin intravenously simultaneously

2 0 191.7 189.0 2.7

30 199.8 133.9 65.9
60 199.5 153.1 46.4
120 268.4 227.6 40.8
180 329.4 314.8 14.6

100 gm. glucose by mouth, 5 units insulin intravenously simultaneously

3 0 181.4 177.1 4.3

30. 159.6 95.3 64.3
60 135.0 94.0 41.0
120 209.0 184.4 24.6
180 220.1 210.3 9.8

100 gm. glucose by mouth, 7 units insulin intravenously 75 min. earlier

4 (-75) (196.0)
(-45) (61.3)
(-30) (35.4)
0 77.5 67.2 10.3
30 213.3 190.1 23.2
60 341.6 317.5 24.1
120 464.4 442.8 21.6
180 445.2 439.0 6.2
 M. SOMOGYI 869

The changes in the rate of glucose assimilation, demonstrated by these

findings, involved changes in both the liver and the peripheral tissues.
While we have no experimental approach at our disposal to demonstrate
this process for the liver in the intact organism (3), changes in the rate of
peripheral assimilation are clearly reflected by changes in arteriovenous
differences. This is well illustrated by the data recorded in Table III.
Comparison of the arteriovenous differences in Tests 2 and 3 with those
in Test 1 shows that 5 units, and even as little as 3 units, of insulin more
than doubled the rate of peripheral assimilation, raising it to a maximum
of 65.9, as against 27 mg. per cent. Incidentally, it may be noted that
3 units of insulin exerted a greater peripheral effect than 5 units. We
have repeatedly described experiments (5, 6) confirming the known fact

Downloaded from http://www.jbc.org/ by guest on September 22, 2018

that higher levels of alimentary hyperglycemia entail higher arteriovenous
differences; i.e., that hyperglycemia acts synergistically with insulin. This
explains why 3 units of insulin increased the arteriovenous differences more
than did 5 units.
In Test 4, in which the adrenal-pituitary system was incited to increased
activity during a hypoglycemic interval, insulin, on the whole, failed to
increase the arteriovenous differences, as is evident when the results of
Tests 1 and 4 are compared. This comparison also illustrates the great
fluidity of the dynamic balance between insulin and its antagonists. It
may be noted that the initial arteriovenous difference in Test 4, directly
before glucose feeding, was 10.3 mg. per cent, a distinct increase over the
normal fasting level. This increase indicates that at this point the action
of insulin was somewhat greater than that of its antagonists; this still was
the case 60 minutes following glucose feeding. From then on, however,
during the next 2 hours, the arteriovenous differences narrowed down con-
siderably, concurrently with very high hyperglycemic levels. This is a
reversal of the normal relationship, as arteriovenous differences normally
increase with increasing alimentary hyperglycemia. This reversal reflects
the fact that, during the 2nd and 3rd hours in Test 4, the insulin-antago-
nistic factors had outstripped the action of the injected insulin. The
tipping of the balance ‘in this direction was due to the gradual fading out
of the injected insulin, on the one hand, and to the continued abnormal
overactivity of the excited adrenal-pituitary system on the other.
The excitation and overactivity of the insulin-antagonistic system is
much greater in diabetic than in normal persons, both in intensity and in
duration. In our healthy subjects normal blood sugar regulation (homeo-
stasis) was restored within a few hours following a hypoglycemic state,
and glucose tolerance became normal by the next day. Quite different
was the response of this diabetic subject. A single hypoglycemic episode,
produced in Test 4, engendered such a persistent overactivity in his insulin-
870 INSULIN HYPOGLYCEMIA

antagonistic system that he excreted 39 gm. of glucose from noon (the

end of Test 4) till the next morning, on the same diet on which he had
been aglycosuric during the preceding 11 months. Also, he remained gly-
cosuric for nearly 5 weeks, even when he was given 5 units of insulin daily
for 1 week and 3 units for a 2nd week. But his glycosuria has gradually
diminished, presumably concurrently with the subsidence of the excited
state of his insulin-antagonistic system. About 5 weeks later he had again
become aglycosuric without insulin injections.
A single hypoglycemic episode in this subject had not only increased
alimentary hyperglycemia (and, in consequence, produced glycosuria), but
also precipitated ketonuria during the first 2 days following Test 4. We
have shown in previous studies that insulin hypoglycemia produces hyper-

Downloaded from http://www.jbc.org/ by guest on September 22, 2018

ketonemia (10, 11) in healthy individuals; hence the same reaction on a
greatly increased scale was not unexpected. After the acute stage of the
adrenal-pituitary excitation had been passed, ketonuria cleared up well
before the glycosuric effect had subsided.

SUMMARY

Previous experiments of the author demonstrated the fact that the ac-
tion of injected insulin, when it is allowed to produce hypoglycemia, is
self-inhibiting, because hypoglycemia enhances the secretion of adrenal-
pituitary hormones whose action is diametrically opposite to insulin. Ex-
periments presented in this paper show that this paradoxical insulin action
greatly increases alimentary hyperglycemia; i.e., that it decreases glucose
tolerance. When insulin is injected simultaneously with the adminis-
tration of 100 gm. of glucose, it accelerates glucose assimilation to such
an extent that alimentary hyperglycemia is completely suppressed. At
the same time arteriovenous blood sugar differences increase as a result of
insulin injection, reflecting an increase in the rate of peripheral glucose
assimilation.
If, however, the injection of insulin precedes the ingestion of glucose by
a brief interval (in these experiments, from 40 to 50 minutes), the hypo-
glycemia that develops during this interval excites the adrenal-pituitary
system to increased activity. As a consequence, alimentary hyperglycemia
is greatly increased and arteriovenous differences are depressed: marked
deterioration of the glucose tolerance takes place.
This diabetogenic effect of insulin hypoglycemia is so effective that it
may produce glycosuria in healthy men. In diabetic persons it takes
place on an exaggerated scale, manifesting itself in marked exacerbation
of the diabetic state: an increase of the already prevalent hyperglycemia
and the accompanying glycosuria and, in addition, ketogenesis.
 hf. SOYOQYI 871

BIBLIOQR4PHY

1. Somogyi, M., J. Bio.?. Chem., 174, 597 (1948).

2. Somogyi, M., J. Biol. Chem., 179, 217 (1949).
3. Somogyi, M., J. Biol. Chem., 186, 513 (1950).
4. Somogyi, M., Endocrinology, 47, 436 (1950).
5. Somogyi, M., J. Biol. Chem., 174, 189 (1948).
6. Somogyi, M., J. Biol. Chem., 179, 1289 (1949).
7. Somogyi, M., Iiirstein, M. B., and Friedewald, W. F., Weekly Bull. St. Louis
Med. Sot., June 10 (1938).
8. Somogyi, M., Proc. Sot. Exp. Biol. and Med., 38, 51 (1938).
9. Somogyi, M., Federation Proc., 7, 190 (1948).
10. Somogyi, M., Proc. Sot. Exp. Biol. and Med., 46, 644 (1940).
11. Somogyi, M., J. Biol. Chem., 141, 219 (1941).

Downloaded from http://www.jbc.org/ by guest on September 22, 2018

EFFECT OF INSULIN HYPOGLYCEMIA
ON ALIMENTARY HYPERGLYCEMIA
Michael Somogyi
J. Biol. Chem. 1951, 193:859-871.

Access the most updated version of this article at

http://www.jbc.org/content/193/2/859.citation

Downloaded from http://www.jbc.org/ by guest on September 22, 2018

Alerts:
• When this article is cited
• When a correction for this article is posted

Click here to choose from all of JBC's e-mail

alerts

This article cites 0 references, 0 of which can be

accessed free at
http://www.jbc.org/content/193/2/859.citation.full.h
tml#ref-list-1