STUDIES OF ARTERIOVENOUS DIFFERENCES IN BLOOD

SUGAR*
IV. EFFECT OF INTRAVENOUS INSULIN AND SIMULTANEOUS
GLUCOSE FEEDING

BY MICHAEL SOMOGYI
(From the Laboratoryof the Jewish Hospital of St. Louis, St. Louis)
(Fteceivedfor publication, March 1, 1949)

This is a report dealing with the effects of insulin upon the rate of

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peripheral glucose assimilation during alimentary hyperglycemia. Avail-
able information on the subject is rather scanty. Cori and Cori (1)
showed that in rabbits the arteriovenous differences were nearly 50 per
cent greater after glucose feeding and simultaneous insulin injection than
after glucose feeding alone. Cori, Pucher, and Bowen (2) observed a
similar response in six out of seven diabetic patients. The limited scope
and nature of the information concerning this subject, which can be
culled from the literature up to 1946, is fairly reflected by a brief r&sumt?
by Peters and Van Slyke (3), in which it is stated that “insulin has rela-
tively little effect on alimentary hyperglycemia of normal subjects. . .
It does tend to curtail the hyperglycemia and to exaggerate the terminal
hypoglycemic reaction.”
We hoped to obtain more detailed facts by means of the procedure
and analytical technique which we employed in our previous studies of
arteriovenous (A-V) differences (4). Healthy young men served as the
subjects in these experiments, each undergoing two tests. First they
were fed 50 to 100 gm. of glucose; in the second test from 3 to 5 units of
insulin were injected intravenously simultaneously with the feeding of
the same amount of glucose as in the first test. Changes in the arterial
(capillary) and venous blood sugar levels were then observed at certain
intervals in the course of 2 to 4 hours. It may be noted that we adhered
to the practice of using rather small insulin doses. This was necessary
in order to avoid, as far as possible, hypoglycemic states, the explicit
purpose of our studies being the observation of insulin action during
hyperglycemia. It will be seen from our results that we were not always
successful in preventing hypoglycemia, even when the insulin dose was
as small as 3 units.
The results of four of these experiments are presented in Table I. As
may be seen, insulin caused marked depression of both the arterial and
* This work wasaidedby the David May-Florence G. May Fund.
1289
1290 INSWLIK ACTIOS DURING HYPERGLYCEMIA

venous blood sugar levels. As a matter of fact, in two subjects (Nos. 1

and 2) the venous blood became hypoglycemic half an hour after the

TABLE I
Showing Response of Healthy Men to Insulin Injected Simultaneously with Oral
Administration vj Glucose

Subject 1 Subject 2

Glucose per 100 CC. ’ Glucose per 100 cc.

Time after A-V A-V
glucose feeding Ab;‘,;kl / Venous difference A;;r;a’ ’ Venous difference
l blood blood

100 gm. glucose by mouth 50 gm. glucose by mouth

hrr. mx. m&T. mg. per cent mg. per ccn1

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mg. w.
0 88.6 86.4 2.2 90.5 86.9 3.6
0.5 162.8 133.7 29.1 161.4 14-4.2 20.2
1 163.4 132.3 31.1 158.8 149.6 9.2
2 114.5 88.6 25.9 71.8 67.0 4.8
3 63.7 62.1 1.6
4 79.7 78.3 1.4

5 units insulin intravenously, 100 gm. 3 units insulin intravenously. and SO gm.
glucose by mouth glucose by mouth

0 87.8 81.0 6.8 90.5

0.5 110.2 58.1 52.1 96.1
1 128.8 111.9 16.9 140.7
2 114.8 89.1 25.7 110.7
3 84.2 82.6 1.6
4 92.9 87.8 5.1
-__-
Subject 4 Subject 5
50 gm. glucose by mouth 100 gm. glucose by mouth
.___- --
0 90.2 86.6 / 3.6 -- 96.1 1 94.5 j 1.6
0.5 203.3 178.8 24.5 165.8 1 142.1 23.7
1 169.6 117.5 52.1 135.1 j 123.7 Ij 11.4
2 62.7 / 54.3 8.4 141.2 115.3 / 25.9
3 127.7 / 110.5 17.2
~__ I
-~__-..
4 units insulin intravenously. 50 gm. 5 units insulin intravenously, 100 gm.
glucose by mouth glucose by mouth
, I
0 83.7 79.9 3.8 97.6 95.9 1.7
0.5 117.2 88.6 28.6 78.3 71.6 6.7
1 114.8 87.8 j 27.0 94.5 74.8 / 19.7
2 70.2 57.0 ; 13.2 113.4 / 100.4 j 13.0
3 120.7 / 97.4 j 23.3
I I
* Arterial glycemic levels were determined in capillary (finger) blood.

administration of glucose and insulin, while the arterial blood sugar,

although substantially lower than in the tests without insulin, had risen
 M. SOMOGYI 1291

above the postabsorptive level. Insulin action was strongest in Subject

5, as shown by the hypoglycemic states in both arterial and venous blood
throughout an hour after the simultaneous administration of 100 gm. of
glucose and 5 units of insulin. From the great depression of alimentary
hyperglycemia it is obvious that the rate of over-all assimilation was
considerably enhanced by as little as 3 units of insulin. Himsworth,
in his brilliant studies dealing with the effect of dietary factors on insulin
action (5), obtained similar results with the oral administration of 50 gm.
of glucose and simultaneous intravenous injection of from 2.5 to 5 units of
insulin.
In regard to the peripheral action of insulin, the central object of these

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studies, the picture presented by our data was not so clear and simple.
In some subjects, at some intervals after injection, the A-V difference
showed that insulin enhanced the assimilation rate. In other subjects,
however, glucose feeding alone increased the A-V differences to nearly the
same extent as did glucose feeding with simultaneous insulin injection,
as if insulin had not at all influenced peripheral assimilation. Finally,
in some instances smaller A-V differences appeared with than without
insulin, conveying the impression that insulin may have inhibited periph-
eral glucose assimilation. All three of these variations appeared even
in a single subject at various time intervals after the injection of insulin.
This is a very confusing picture, indeed, but only until one applies to
its interpretation two facts which we presented in previous papers. One
of these facts is the close relationship that obtains between the extent
of hyperglycemias and the magnitude of A-V differences; we have shown
that in any healthy person increasing hyperglycemic levels entail increas-
ing A-V differences (4). The second pertinent fact concerns the influence
of hypoglycemia on A-V differences; we have found that hypoglycemia
activates an insulin-antagonistic mechanism, with the consequence that
peripheral insulin action is counteracted during hypoglycemic states, and
this is reflected in a shrinkage of A-V differences (6, 7). Erroneous con-
clusions can be avoided only if our results are analyzed in the light of
these two facts.
In Subject 1 (Table I), for instance, the A-V difference increased to
52.1 mg. per cent in the course of 4 hour after insulin injection, whereas
with glucose feeding alone it had gone up to only 29.1 mg. per cent. This
difference between the two responses, attesting to a marked action of
insulin, is further accentuated by the fact that the greater increase oc-
curred in spite of a lower hyperglycemic level. At the end of the second
half hour period the A-V difference has appreciably decreased in the test
with insulin. This, however, is the invariable sequel to the emergence
of hypoglycemia in the venous blood, a sharp dip to 58.1 mg. per cent,
which activated the insulin-antagonistic mechanism, which in turn frus-
1292 INSULIN ACTION DURING HYPERGLYCEMIA

trated peripheral insulin action. This defense reaction against hypo-

glycemia prevailed only until the hypoglycemic effect of insulin had been
successfully combated and the excitation of the insulin antagonists had
subsided. This was attained at the end of the 2nd hour, when the blood
sugar again rose above the fasting level; at this point the A-V difference
showed again a substantial increase.
In a previous paper (7) we stated that it is arterial hypoglycemia that
activates the insulin antagonists, while venous hypoglycemia fails to
exert such an effect so long as the arterial blood sugar stays above its
postabsorptive level. In those experiments, however, which led to this
conclusion, the venous hypoglycemias were of rather slight degrees,
whereas in the present experiment (Subject 1) the venous blood sugar

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decreased sharply by 22.9 mg. per cent within 3 hour. Venous hypo-
glycemias of such substantial degrees apparently do stimulate the insulin-
antagonistic mechanism, even while the arterial blood sugar maintains
moderate hyperglycemic levels.
That venous hypoglycemia of a minor degree exerts far less of this
effect is shown by the response of Subject 2, who received only 3 units
of insulin. As may be seen in Table I, this subject also developed venous
hypoglycemia $ hour after insulin injection, but the dip was only 10.8
mg. per cent below the fasting level and apparently caused less shrinkage
in the A-V difference than did the more intensive hypoglycemia in Sub-
ject 1. It may be noted that the A-V difference at the half hour period
in Subject 2 was much the same with and without insulin. If, however,
one takes into consideration that in the test with glucose feeding alone a
hyperglycemic level of 164.4 mg. per cent was necessary to produce a
20.2 mg. per cent A-V difference, it is evident that in the second test it
was the action of the injected 3 units of insulin that produced an A-V
difference of the same magnitude, i.e. 20.5 mg. per cent, practically without
any of the synergistic effect of hyperglycemia. It may be said, then,
that the 3 units of insulin alone effected the increase in the rate of periph-
eAtal assimilation, since our past experiments indicate that the slight
rise of merely 5.6 mg. per cent in the arterial blood sugar that took place
in Subject 2 does not measurably affect the A-V difference (4). This ex-
periment shows emphatically the powerful stimulus upon the rate of
peripheral glucose assimilation which can be exerted by as little as 3
units of insulin.
Subject 5 deserves especial attention because of his greater sensitivity
to insulin (see Table I). In response to 5 units, injected simultaneously
with the oral administration of 100 gm. of glucose, he promptly developed
hypoglycemia not alone in the venous, but also in the arterial, blood, and
the hypoglycemic state persisted through the entire 1st hour. This means
 M. SOMOGYI 1293

that insulin action was so potent that the rate of intestinal absorption of
ghrcose was unable to cope with the rate of assimilation. The resulting
hypoglycemia then activated the insulin-antagonistic mechanism. This
reaction, as we know, is especially responsive to arterial hypoglycemia
(7). As a consequence, the A-V difference increased to only 6.7 mg.
per cent at the half hour period, a response resembling that observed after
the injection of a similar dose of insulin in the postabsorptive state
(6). Small as this increase in the A-V difference is, it still testifies to the
fact that insulin action outstripped the antagonistic factors at the half
hour period, but the balance was only slightly positive in favor of the
insulin. During the second half hour interval, however (i.e., between
30 and 60 minutes after injection), when the arterial blood sugar had

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nearly reverted to the postabsorptive level, the excitation of the insulin-
antagonistic mechanism began to subside and insulin action gained gradual
ascendency over it. As a result, the A-V difference increased at the
end of this period to the substantial value of 19.7 mg. per cent, despite
the continuing absence of arterial hyperglycemia, and despite the per-
sistence of venous hypoglycemia. Insulin action here was quite powerful,
more so than that indicated by the A-V difference, since the latter reflects
the action of only that fraction of the 5 units which was not counteracted
by the antagonistic factors.
The response of Subject 4 (Table I) differed from that of the preceding
three in that he developed no hypoglycemia after glucose feeding and
the simultaneous injection of insulin. Nor did hyperglycemia reach any
substantial degree. In fact, the action of 4 units was potent enough to
prevent the venous blood sugar from rising higher than 88.6 mg. per cent
at any time during the absorption of 50 gm. of glucose. This is in sharp
contrast of 178.8 mg. per cent of venous hyperglycemia that developed after
glucose feeding alone. Irrespective of the pronounced insulin action in
the body as a whole, however, a distinctly lower peripheral assimilation
rate is apparent in Subject 4 with than without insulin, as if insulin had
acted as an inhibitor. Unlike the other three cases, no hypoglycemia
had occurred in Subject 4; so that the lower A-V differences in the second
test are entirely due to the fact that the blood sugar stayed at relatively
low levels after insulin injection. As may be noted in Table I, the maxi-
mal arterial hyperglycemia after the ingestion of 50 gm. of glucose in
this instance was 203.3 mg. per cent, whereas when 4 units of insulin were
injected simultaneously with glucose feeding the maximum was only
117.2 mg. per cent. This great discrepancy was the factor which so
effectively masked the action of insulin on peripheral assimilation, a
factor which requires correction if valid comparison of the two tests is
to be made.
1294 INSULIN ACTION DURING HYPERGLYCEMIA

While it appears impossible to find a way for a quantitative correc-

tion of the effect of the insulin-antagonistic factors, we can offer a formula
which permits of correction for differences in the hyperglycemic levels.
The correction involves the following steps. In the first place, we add up
the A-V differences that were determined at various intervals during ali-
mentary hyperglycemia, and designate this sum as the “peripheral assimi-
lation index.” This sum, introduced in a previous study (6), furnishes
an integrated picture of the peripheral assimilation for the entire period
of the experiment. Likewise we summarize the increment in the arterial
glycemic level at the corresponding intervals and denote this sum as the
“hyperglycemic sum.” For comparison of peripheral assimilation rates
obtained in two experiments, the ratios, assimilation index to hyperglyce-

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mic sum, are brought to a common denominator. This correlation of the
data yields the “relative assimilation index,” which permits comparison
of two assimilation indices with the elimination of the influence of the
difference in the hyperglycemic levels. This calculation is based on the
premise that, in any single healthy person, the increase in A-V differences
during alimentary hyperglycemia is roughly proportional to the increase
in the arterial glycemic level. Hence, if any added factor, as for instance,
injected insulin, changes this relationship, the change can be ascribed to
the action of this added factor. It is inherent in the nature of physiologic
processes that our premise is of limited validity, but calculations on a
number of examples convinced us that the relative assimilation index is
a useful tool for the evaluation of changes in A-V differences whenever
the influence of the hyperglycemic factor is to be discounted in order to
permit accounting for the effect of another factor.
An example given in Table II may help to elucidate the meaning and
calculation of the relative assimilation index. Two tests are recorded
here which were performed on a healthy person. Although identical
doses (50 gm.) of glucose were administered in both tests, considerably
higher hyperglycemic levels were produced in the second test by injec-
ting part of the glucose (15 gm.) intravenously and feeding by mouth
only the remaining 35 gm., whereas in the first test all of the glucose was
fed by mouth. It may be seen that, in line with our past observations
(4), the higher hyperglycemic levels entailed greater A-V differences.
This is expressed in the assimilation index, which in the second test was
75, as against 47 in the first test, a difference of about 70 per cent. Now,
if, by applying the formula given in the foot-note below Table II, one
reduces the assimilation index of the second test to the same lower hyper-
glycemic level that prevailed in the first test, one obtains the relative
assimilation index for the second test. This figure (Column 7, Table II)
means that the assimilation index of the second test would be approxi-
 M. SOMOGYI 1295

mately 41.6 if the hyperglycemic levels were the same as in the first test.
Comparison of this relative assimilation index with the actual assimilation
index of the first test (which was 47.2), shows a close agreement between
the two. (A similar agreement is, of course, in evidence when one calcu-
lates the assimilation index of the first test for the hyperglycemic levels
of the second test; this figure, 85.2, is fairly close to 75.0, the actual as-
similation index of the second test.)
This is the approach we used for the evaluation of insulin action on the
TABLE II
Method of Calculation of Assimilation Index and Relative Assimilation Index

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60 gm. glucose by mouth
brs. mg. fi#?cm: et&s.)rn cml m*. gc?cent
0 (33.6) 0 (6.0)
0.6 94.4 6.8 19.4

: 121.6
102.6 14.0
32.9 11.6
16.2 62.7 47.2 (35.2)

15 gm. glucose intravenously, 35 gm. by mouth

0 (89.1) 0 (6.5)
0.5 161.7 72.6 43.2
1 103.3 19.2 21.9
2 92.6 3.6 9.9 96.3 76.0 41.6

* Sum of quantities in Column 3.

t Sum of quantities in Column 4.
95.3
$75.0 x 2 - 41.6, or 47.2 X - - 35.2.
62.7

rate of peripheral assimilation during alimentary hyperglycemia. For

each subject we calculated the relative assimilation index for the first
test; i.e., we calculated what the assimilation index would be after glucose
feeding alone if the hyperglycemic levels had not risen higher than in the
tests in which insulin was injected simultaneously with glucose feeding.
The data used in the calculations, and the results, recorded in Table III,
illustrate how misleading it would be to evaluate insulin action on the
basis of A-V differences without being aware of their relationship to the
glycemic levels. From the magnitude of the actual assimilation index
(sum of A-V differences), one would conclude that in only two of our five
subjects (Nos. 1 and 2) did an increase in the rate of peripheral assimila-
1296 INSULIN ACTION DURING HYPERGLYCEMIA

tionoccur as a result of insulin injection, and even that increase was insig-
nificant. In one subject (No. 3) there was no change, while in two others
(Nos. 4 and 5) insulin seemingly depressed peripheral assimilation. But
the picture changes if we consider the relative assimilation index, the value
of which is given in the last column of Table III. Comparison of the two
tests on this basis shows in every instance a definite enhancement of the
peripheral glucose assimilation by injected insulin. When this effect was
seemingly absent, it was partly due to the depression of the alimentary
hyperglycemia in the tests with insulin injection, and partly to the handi-
cap under which insulin labored when hypoglycemic states led to the
mobilization of insulin-antagonistic factors.

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TABLE III
Showing That, Relative to Hyperglycemic Levels, Peripheral Glucose Assimilation Is
Enhanced by Insulin Injected Simultaneously with
-
Glucose Feeding
-

1Insulin dose
Rise of arterial blood sugar above fastin level,
and A-V differences, at intervals of
- I Hyper-
:lycemi
I lelative
assimi-
0.5 hr. 1 hr. 2 hrs.
sum 22;
Blood A-V Blood A-V Blood A-V
sugar sugar sugar
-- --- --
units
None 74.2 29.1 74.8 31.1 25.9 25.9 174.9 86.1 44.6
5 22.4 52.1 41.0 16.9 27.0 25.7 90.4 94.7
None 73.9 20.2 68.3 9.2 -18.7 4.8 142.2 34.2 17.8
3 5.6 20.5 50.2 8.1 20.2 14.6 76.0 43.2
None 92.6 31.4 105.3 49.2 24.5 29.1 222.4 99.7 84.4
5 97.0 45.1 49.5 26.7 41.7 27.3 188.2 99.1
None 113.1 24.5 79.4 52.1 0.4 8.4 192.9 85.0 28.6
4 33.5 28.6 31.1 27.0 -13.5 13.2 64.4 68.8
None 69.7 23.7 39.0 11.4 45.1 25.9 153.8 61 .O 6.3
5 -19.3 6.7 -3.1 19.7 15.8 13.0 15.8 39.4
- -

SUMMARY

Alimentary hyperglycemia of healthy persons is effectively suppressed

by insulin when injected intravenously and simultaneously with oral
glucose feeding. Doses as small as from 3 to 5 units may cause hypogly-
cemic states in subjects who, without injected insulin, develop substantial
degrees of hyperglycemia after ingestion of the same amount of glucose.
This fact indicates that the physiological insulin requirement of healthy
persons is very small.
Insulin effect on the rate of peripheral assimilation during alimentary
hyperglycemia cannot be judged on the basis of A-V differences (and the
assimilation index), without taking into account two factors: (I) the
 M. SOMOGYI 1297

insulin-antagonistic sequel of hypoglycemia, and (2) the functional re-

lationship between hyperglycemic levels and A-V differences. The first
of these two factors is not amenable to measurement. An approxi-
mately quantitative correction for the influence of the hyperglycemic
factor, however, is feasible. If such a corrected quantity, designated as
the (‘relative assimilation index,” is used for evaluation of A-V differences,
it was found that insulin invariably enhances the rate of peripheral glucose
assimilation when injected intravenously simultaneously with glucose
feeding.
BIBLIOGRAPHY

1. Cori, C. F., and Cori, G. T., Proc. Sot. Exp. Biol. and Med., 22, 72 (1924).

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

2. Cori, C. F., Pucher, G. W., and Bowen, B. D., Proc. Sot. Exp. Biol. and &fed., 21,
122 (1923).
3. Peters, J. P., and Van Slyke, D. D., Quantitative clinical chemistry; Interpreta-
tions, Baltimore, 2nd edition, 1, 226 (1946).
4. Somogyi, M., J. Biol. Chem., 174, 189 (1948).
5. Himsworth, H. P., Clin. SC., 1, 1 (1930).
6. Somogyi, M., J. Biol. Chem., 179, 217 (1949).
7. Somogyi, M., J. Biot. Chem., 174, 597 (1948).
 STUDIES OF ARTERIOVENOUS
DIFFERENCES IN BLOOD SUGAR: IV.
EFFECT OF INTRAVENOUS INSULIN
AND SIMULTANEOUS GLUCOSE
FEEDING
Michael Somogyi
J. Biol. Chem. 1949, 179:1289-1297.

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