KETONE-SPARING EFFECT OF GLUCOSE

BY MICHAEL SOMOGYI AND T. E. WEICHSELBAUM

(From the Laboratory of the Jewish Hospital of St. Louis, St. Louis)

(Received for publication, June 29, 1942)

From time to time reports have appeared to the effect that animals that
are in a state of ketosis show an increase in the excretion of ketone bodies
after the administration of carbohydrates. This phenomenon is incom-
patible with the theory, until recently generally accepted, that carbohy-
drates exert a ketolytic action in the organism (“Fats burn only in the fire of
carbohydrates”). If the theory were valid, carbohydrate feeding could

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produce only two possible results: it would either decrease ketosis, or, if the
organism has completely lost its ability to utilize carbohydrates, ketosis
would remain unchanged. An increase of ketosis is incompatible with the
theory. Since, however, it does occur, some authors tried to reconcile the
fact with their theory by assuming that the glucose “flushes out” and
forces into circulation the ketone bodies that have been accumulating in
the tissues. This assumption, rather uncritical and arbitrary, is untenable
in the light of the work of Harrison and Long (1) who found that in rats
the muscle cells are entirely free of ketone bodies until the ketonemia
reaches very high levels, and even then the concentration within the cells
is much lower than in the blood. As to the liver, these authors have found
no higher concentrations of ketone bodies in the intracellular than in the
extracellular fluid.

Observations on Diabetic Patients

Our observations on diabetic patients disclosed the fact that an increase
in ketonemia and ketonuria, as a result of glucose feeding, is the rule rather
than the exception in nearly all cases which show ketonemic levels not lower
than 15 to 20 mg. per cent (expressed in terms of /3-hydroxybutyric acid).
Three examples, presented in Table I, illustrate the phenomenon. The pa-
tients in these experiments were fed 100 gm. of glucose about 14 hours after
their last meal. Blood samples, obtained directly before and at certain
intervals after the administration of glucose, were analyzed for glucose and
ketone bodies by methods previously described (2,3). As the results show,
ketonemia increased within 1 hour after glucose feeding and stayed above
the postabsorptive level throughout the entire period of observation (4
hours). The rise was considerable in all instances; thus, in Case 1 the post-
absorptive ketone content of 62.9 mg. per cent was nearly doubled in 4 hours
after glucose feeding. Analysis of the urines during these observations
567
568 KETONE-SPARING EFFECT OF GLUCOSE

ruled out renal retention as a possible cause of the increase in ketonemia; in

Case 3, for instance, the excretion of ketone bodies amounted to 202 mg.
during the lst, and to 539 mg. during the 4th hour.
As pointed out before, this increase in ketosis defies explanation on the
basis that glucose exerts a ketolytic action in the human organism. It can
be readily explained, however, in the light of extensive and well documented
experimental evidence which has been accumulating in recent years.1 One
can postulate on the basis of this evidence that the ketone bodies that are
transported in the blood and excreted in the urine are produced in the liver
(with some exceptions, perhaps, under extreme conditions). The liver,
namely, is unable to burn any appreciable amounts of ketone bodies; hence

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TABLE I
Eflect of Glucose Feeding upon Ketonemia in Diabetic Patients with Severe Ketosis

Case No. Time after Blood sugar Acetoacetic Total ketone

I:lucose feeding acid bodies

hrs. mg. ger cent mg. per cent mg. per cent mg. per cent
0 433 21.8 41.1 62.9
1 575 28.6 59.7 88.3
2 583 25.7 58.4 84.1
3 560 34.9 75.5 110.4
4 548 34.4 84.7 119.1
0 393 24.9 43.2 68.1
1.5 544 31.1 50.8 81.9
3.5 635 37.4 63.9 101.3
0 243 / 7.8 17.6 25.4
0.5 354 10.5 30.4 40.9
1 435 10.0 27.5 37.5
2 503 11.0 22.2 33.2
3 524 9.2 29.1 38.3
4 403 13.6 29.5 43.1

when it metabolizes fats (and proteins), it delivers to the blood ketone

bodies as the end-products of its fat catabolism. The larger the amount of
the fats that are catabolized in the liver, the larger is the amount of ketone
bodies passed on to the blood.
Muscle and other extrahepatic tissues, on the contrary, oxidize fat com-
pletely, without inhibition at the 4-carbon atom stage. In addition, they
are capable of oxidizing considerable amounts of ketone bodies that are
furnished by the liver (or, for that matter, exogenous ketone bodies injected
into the organism). But the capacity of muscle to utilize ketone bodies is
1 Discussion and bibliography concerning the subject may be found in compre-
hensive articles by Stadie (4), Soskin and Levine (5), and Mirsky (6).
 M. SOMOGYI AND T. E. WEICHSELBAUM 569

limited; thcreforc, when the rate of hepatic production exceeds the rate of
peripheral utilization, hyperketonemia and ketonuria ensue. Thus the
ketone body content of the blood represents a balance between the amount
of ketone bodies produced in the liver, on the one side, and that utilized in
the extrahepatic tissues and excreted in the urine, on the other.
The accompanying, diagram based on this concept, presents the known
and possible factors which can affect the ketonemic level. It may be noted
Ketonemic level
I I
Is increased by Is decreased by
r---- -__
1 IT------:
Deglycobenation Decreaw in Increabed CHO Increale in

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of liver, en- rate of ketone utilization in rate of ketone
tailing an in- utilization in liver, which utilization in
crease in its extrahepatic depresses fat extrahepatic
fat catabolism tissues catabolism tissues
(Factor I) (Factor II) (Factor III) (Factor IV)

that an increase in ketonemia may be due to two factors. The first of these
(Factor I), deglycogenation of the liver, invariably augments the rate of
production of ketone bodies and, as a consequence, the ketonemic level.
This factor can be safely ruled out under the conditions of our observations.
As a matter of fact, the increase of hyperglycemia, resulting from glucose
feeding, is known to enhance deposition of glycogen in the liver (7). This
influence of hyperglycemia is effective also in diabetic conditions, as it has
been shown that even the livers of completely depancreatized dogs store
glycogen temporarily (8) and at the same time ketone production dimin-
ishes (9) at very high glyccmic levels.
It is inconceivable, therefore, that glucose feeding should increase the
production of ketone bodies in our diabetic subjects. Thus the increase of
ketonemia that occurs can be explained only by a decrease of utilization in
the extrahepatic tissues (Factor II in the diagram). So long as the muscles
have a poor carbohydrate supply (low glycogen reserve), as in the case of the
muscle tissues in diabetic subjects, especially in the postabsorptive state,
these tissues utilize considerable portions of the ketone bodies that are
supplied by the liver. After glucose feeding, however, when glucose reaches
the tissues in substantially increased concentrations, the rate of carbohy-
drate utilization in the muscle cells is greatly enhanced (even in depan-
creatized animals) and, in consequence, the utilization of ketone bodies is
depressed.
When employing the expressions fat-sparing effect, protein-sparing effect
of carbohydrate, we recognize the tendency of the mammalian organism to
oxidize carbohydrate in preference to other metabolites. In the instance of
our observations, when carbohydrate is made available in the muscle tissues
570 KETONE-SPARING EFFECT OF GLUCOSE

of diabetic subjects, its preferential oxidation leads to the sparing of ketone

bodies, a process which manifests itself in an increased ketonemic level.
This competition for oxidation was demonstrated also in isolated organs.
Edson (10) has shown that in liver slices fats are oxidized (leading to an
increased production of ketone bodies) only when no carbohydrate is avail-
able; as soon as carbohydrate enters the metabolic mixture, it is oxidized in
preference to fat and, in consequence, the production of ketone bodies is de-
pressed. Waters et al. (11) have demonstrated a ketone-sparing effect of
glucose in heart-lung preparations.
It is evident that the ketone-sparing effect of glucose in the extrahepatic
tissuescan manifest itself in increased ketonemia only when the liver utilizes
none or only slight quantities of the carbohydrate that is offered to it. For,

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if the liver is able to utilize appreciable amounts of carbohydrate, the sup-
pression of fat oxidation leads to a decrease in the production of ketone
bodies (Factor III), and this change may cancel or outstrip the opposite
change in the extrahepatic tissues. We have actually observed such
responsesto glucose feeding in some casesof diabetic ketosis. In Case 4,
for example (Table II), a continuous drop in the ketonemic level has taken
place following the 1st hour after glucose feeding, until the postabsorptive
ketonemic level of 14.5 mg. per cent has dropped to 5.5 mg. per cent by the
end of the 4th hour. In Cases5 and 6, asit may be noted, the decreasehas
gone so far as to end in normal ketonemic levels of 0.8 and 0.6 mg. per cent,
respectively, within 3 hours after the administration of glucose (the normal
range is 0.3 to 0.9 mg. per cent). This responseis much the sameas that of
healthy individuals who developed ketosis by fasting or restriction of car-
bohydrate intake.
There is, however, no sharp line of demarcation between caseswith high
and low degreesof ketosis. In Case 8, for instance, glucose feeding caused
an increase in ketonemia, although the postabsorptive level was as low as
3.8 mg. per cent. Case 7 was similar in character. Case 12, on the other
hand, with a high postabsorptive ketonemic level of 42.8 mg. per cent,
responded to glucose feeding as did the milder cases,in that the ketonemia
declined after glucose feeding and stayed below the initial level throughout
the 4 hours of observation.
Finally, it can scarcely escapeattention that in many casesthe ketonemic
level shows notable fluctuations. It may first drop below the postab-
sorptive level only to rise subsequently above and again drop below it, as in
Cases10 and 11 (Table II). In other instances one enc’ounters fluctuations
but with the ketonemia always staying above the postabsorptive level, as in
Case3 (Table I) and Cases7 and 12 (Table II).
All of these variations can be readily understood by consulting our dia-
gram. Factor III, acting by way of carbohydrate utilization in the liver, is
 M. SOMOGYI AND T. E. WEICHSELBAUM 571

apparently still effective to some extent in diabetic patients, particularly

during high alimentary hyperglycemia. This process tends to decrease
ketonemia by inhibiting the production of ketone bodies. Simultaneously
Factor II, in the extrahepatic tissues, acts in the opposite direction. The
balance between the two factors decides the ketonemic level. Whenever
the effect of Factor II is greater than that of Factor III, ketonemia in-

TABLE II
Effect of Glucose Feeding upon Ketonemia in Diabetic Patients with Mild Ketosis
Total ketone bodies are calculated as fl-hydroxybutyric acid.

Case 4 Case 5 Case 6

Time after
-

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glucose feeding
Blood sugar Ketone bodies Blood sugar Ketone bodies Blood sugar Ketone bodies

hrs. mg. per cent v&g. per cent mg. per cent mg. per cent nzg. per cent mg. per cent
0 286 14.5 308 7.4 175 5.5
1 335 16.1 438 3.6 282 3.9
2 475 10.9 454 2.8 335 1.1
3 503 6.0 405 0.8 323 0.6
4 417 5.5 355 1.0 333 0.6

Case 7* Case 8 Case 9

0 202 12.1 368 3.8 273 11.0

1 375 19.1 643 3.7 395 7.3
2 446 20.0 544 4.7 453 4.5
3 451 15.4 495 4.2 473 4.6
4 353 18.9 434 4.9 375 4.7

Case 10 Case 11 Case 12

-
0 178 4.4 234 7.6 238 ’ 42.8
0.5 263 3.8 337 5.7 432 42.9
1 343 6.7 367 7.9 483 35.4
2 380 2.2 364 3.2 527 26.2
3 408 2.2 329 5.8 397 36.0
4 328 3.1 301 5.8 312 26.4
-
* This patient was the only one among the cases presented in Tables I and II who
had been treated with insulin prior to our observations.

creases, and, conversely, when the rate of Factor II lags behind the rate of
Factor III, ketonemia decreases. Continued shifts in the relationship be-
tween the rates of action of these two factors entail corresponding fluctua-
tions in the ketonemic level. That Factors I and IV could not have had
any part in the changes of ketosis under the conditions that prevailed in our
experiments, is, we believe, obvious.
572 KETONE-SPARING EFFECT OF GLUCOSE

Observations on Dogs
Subtotally (about 80 to 90 per cent) depancreatized dogs, as it is known,
are able to utilize normal amounts of carbohydrate without developing any
symptoms of diabetes. They show neither glycosuria nor ketosis, and their
postabsorptive blood sugar level is normal so long as they are kept on a diet
consisting of lea,n meat, bones, and Purina chow. It was found in this
laboratory that when such dogs were switched to a diet of 2 parts of meat
and 1 part of fat they gained weight and developed glycosuria and ketosis.
Postmortem examinations disclosed that the livers had become deglyco-
genated and very fat (fat content of from 16 to 20 per cent). These condi-
tions are not produced by a similar dietary rkgime in dogs in which the

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pancreas is intact (unpublished observations).
Dogs, after having been made diabetic in this manner, were employed for
experiments similar to those we have performed on diabetic patients. The
animals were fed by stomach tube 2 gm. of glucose per kilo of body weight,
in some instances in the postabsorptive state, in others after 3 to 4 days of
fasting, and the changes in the glycemic and ketonemic levels were observed
at certain intervals. In Table III it may be seen that a dog, while kept on a
normal diet, showed only a moderate deviation from the glucose tolerance of
intact animals. As to the ketonemia, the postabsorptive level was within
the normal range. After the administration of glucose an initial drop
occurred, then a slight rise, but the changes were within the normal range
(such changes we have also observed in healthy men). After, however, the
dog had been rendered diabetic by fat feeding, glucose feeding caused t.he
ketonemia to rise considerably above the initial level.
In Table IV are presented two experiments on other animals that were
rendered glycosuric and ketonuric by meat-fat diets. These dogs were
fasted 4 days before the experiment. As may be seen, the changes in the
ketonemia of Dog D were quite similar to those in many diabetic men; in
the 1st hour after glucose feeding there was a transitory decline, but at the
end of the 4th hour ?n increase of about 60 per cent above the postabsorp-
tive level has occurred. By the end of the 6th hour a further substantial
increase has taken place, raising the ketonemia to 3-fold of the post.-
absorptive level.
In Dog C the relationship between the glycemic and ketonemic levels is
more obvious than in any of the other experiments described in this paper.
During the first 1.5 hours after glucose feeding carbohydrate utilization in
the liver was slight, so that the production of ketone bodies was not ap-
preciably inhibited, while in the extrahepatic tissues carbohydrate began to
compete with the ketone bodies for oxidation, thus exerting a ketone-spar-
 M. SOMOGYI AND T. E. W%IC!HSELBAUM 573

ing effect. The balance of the two processes was manifested in an increase
of the ketonemic level (Factor II > Factor III, according to the diagram).
Subsequently, when t,he blood sugar lingered at the high concentration of
803 mg. per cent’, t’he liycr was enabled to store some glycogrn and to
catabolize increased quantities of ca,rbohydrate, so that the effect of Factor
TABLE III
E,ffects of Glucose Feeding in Postnhsoqhive State upon Ketonemia in Subtotall~y
Depancreatizcd Dogs
2 gm. of glucose per kilo of body weight, given by stomach tube.

4 mos. after operation, 5 weeks on

10 wks. after operation, on normal diet
Time after glucose fat-meat diet
feeding -

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Blood sugar Blood ketones Blood sugar Blood ketones

hrs. mg. per cell1 mg. per cm1 mg. per cent mg. $Jer cent
95 0.9 242 13.1
233 0.4 460 4.3
295 0.4 369 11.3
158 0.6 310 15.1
95 0.7 308 18.1

TABLE IV
Eflects of Glucose Feeding upon Ketonemia in Subtotally Dcpnncreafised (Fat-Fed)
Dogs, after a Fast of /t Days

Dog C* n0g Di
Time after glucose
feeding
Blood sugar Blood ketones Blood sugar Blood ketones
___. ..-
hrs. mg. per cent mg. per cent

0.0 278 1.7

0.25 302 1.8
0.5 515 2.1
1.0 674 2.2 354 3.4
1.5 752 3.3
2.0 803 2.6 299 5.6
4.0 803 1.4 263 9.1
6.0 441 6.1 239 15.2

* 4 gm. of glucose per kilo of body weight.

t 2 gm. of glucose per kilo of body weight.

III outstripped the effect of Factor II, a shift, that came to expression in a,
diminished ketonemia. Hut by 6 hours after glucose feeding, when the
blood sugar has dropped steeply, carbohydrate utilization in the liver de-
clined, the etiect of Factor III diminished, and once more Factor II out-
stripped Factor III, resulting in a great increase of the ketonemic level.
574 KETONE-SPARING EFFECT OF GLUCOSE

SUMMARY

It has been recognized in recent years that carbohydrates exert no

ketolyt’ic effect in the organism and that, the phrase, “Fats burn only in the
fire of carbohydrates,” is unfounded. Now experimental evidence is ac-
cumulating to demonstrate the contrary; namely, t.hat carbohydrates exert
a ketone-sparing effect in various extrahepatic (in the main, muscle) tissues
and, as a consequence, inhibit the burning of ketone bodies.
This sparing effect manifests itself after glucose feeding in an increase of
the csisting ketoncmia (and ketonuria) of diabetic patients. The rise in
krtonemia occurs, however, only in casesin which t,he ability of the liver to
utilize carbohydrates is greatly impaired, so that the liver continues to use
fats (and proteins), and hence to produce ketone bodies, at, nearly the same

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rate as before glucose feeding.
Sulbt,otally depancreatized dogs, whose livers had been rendered very fat
(16 to 20 per cent fat content) by protracted administration of high fat
dirts, develop glycosuria and ketosis. Such animals respond ‘to glucose
feeding with an increase in ketonemia and ketonuria in the same manner
as diabetic men.
BIBLIOGRAPHY

1. Harrison, H. C., and Long, C. N. H., J. Biol. Chem., 133, 209 (1940).
2. Shaffcr, P. A., and Somogyi, M., J. Biol. Chem., 100, 695 (1933).
3. Weichselhaum, T. E., and Somogyi, M., .I. Biob. Chem., 140, 5 (1941).
4. St&e, W. C., .I. C/in. Znv., 19, 843 (1940).
5. Soskin, S., and Levine, R., in Lewis, H. B., Biological symposia, Lancaster, 6,
64 (1941).
6. Mirsky, I. A., J. Am. Med. Assn., 118, 690 (1942).
7. Cori, C. F., and Cori, C. T., J. Dial. Che?n., 86, 275 (1929-30).
8. Minsky, I. A., IIcimau, J. D., and Broh-Kahn, R. II., .Irn. J. Physiol., 118, 290
(1937).
9. Bode, 11. C., Co Tui, F., and Faxbcr, L., A~I. J. I’hysiol., 103, 18 (1933).
10. Edson, N. I,., Riochem. J., 30, 1862 (1936).
Il. Waters, E. T., Fletcher, J. P., and Mirsky, I. A., Am. J. Physiol, 132, 542 (1938).
 KETONE-SPARING EFFECT OF
GLUCOSE
Michael Somogyi and T. E. Weichselbaum
J. Biol. Chem. 1942, 145:567-574.

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