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EFFECTS OF GLUCOSE FEEDING UPON THE KETONEMIA IN

HEALTHY MAN
BY MICHAEL SOMOGYI
(From the Laboratory of the Jewish Hospital of St. Louis, St. Louis)

(Received for publication, July 27, 1942)

Normal human blood a.lways contains b-hydroxybut)yric acid and aceto-


acetic acid; the sum of the two acids, expressed in terms of P-hydroxybu-
tyric acid, is less than 1 mg. per cent, and amounts on an average to 0.5 mg.
per cent (1). The blood samples which yielded these values were drawn
in the* postabsorptive state (before breakfast), while blood samples ob-

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tained between meals tended to show lower ketonemic levels. This
observation prompted a study of the possible changes in the ketonemia of
healthy individuals after the administration of 100 gm. of glucose.
Since the changes involved were very small in absolute values, considcr-
able quantities of blood had to be used, even with a sensitive micronnalyti-
cal method. The blood was deproteinized by diluting 20 to 25 cc. of blood
with 2 volumes of 0.3 N barium hydroxide solution and by the addition
(10 to 15 minutes later) of 2 volumes of 5 per cent zinc sulfate solution.
The mixture was thoroughly shaken and centrifuged before filtration.
This Method of deproteinization was described in detail in a previous paper
(1). To avoid further dilution, the filtrate (diluted 1: 5) was desaccharified
by Salkowski’s method, with use of anhydrous copper sulfate and calcium
hydroxide in substance. Of this filtrate 50 to 60 cc. (corresponding to 10
to 12 cc. of blood) were used for the determination of acet~oncctic an.d
p-hydroxybutyric acids by a method previously described (1).
Result,s so obtained are presented in Table I. They show that’ t,he
ketonemic level decreases by 30 and occasionally by more than 50 per cent,
at one time or anot’her, wit’hin 3 hours after the administration of glucose.
(We have encountered but few cases, in which the very low postabsorpt#ive
ketonemic level has undergone no detectable change, as, for example, in
the last two subjects in Table I.) In the 4th hour the ketonemia begins
to increase and approaches the postabsorptivc level, but does not rise
above it either at this time or an hour or two later.
We have encountered cases, however, in which the ketonemia, after an
initial dip, has risen well above the postabsorptive level during the 4th
or 5th hour interval after the administration of glucose. In some instances
a substantial increase appeared only during the 6th hour. Such changes
occurred exclusively in subjects in which the alimentary hyperglycemia
was followed by variable degrees of hypoglycemia. In Case 1 (Table Ii),
575
576 EFFECTS OF GLUCOSE ON KETONEMIA

for instance, as the blood sugar has risen to high levels during the 1st hour
after the administration of glucose, the ketone bodies dropped by 45 per
cent below the postabsorptive level. In the 3rd and 4th hours, however,
when the blood sugar receded to the low level of 50 mg. per cent, keto-
nemia increased and exceeded the lowest previous level by 272 per cent,
and t>hc postabsorptive level by 104 per cent. Cases 2, 3, and 4 show
changes of the same character t’o an even more pronounced degree.
The observations on the last two casts given in Table TI mere made on
healthy students after 3 days of fasting. As may be noted, in Case 5

TABLE I
Showing !l’hat Postabsorptive h’etonemic Level of Healthy Individuals Ikdines within

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3 Houis after Glucose Feeding
The kctorlc hodics arc calculated as my. of P-hydroxybutyric acid per 100 cc.
of blood.

Time after administration of glucose


Subject ___-
O hr. 1 hr. 2 hrs. 3 hrs. 4 1115.
-____
I,. M., 43 yrs., M.. t.. 0.51 0.58 0.36 0.47
A. I~., 51 Cl i( .,., 0.66 0.36 0.36 0.26 0.50
T,. w., 37 “ F.. 0.73 0.24 0.39 0.26 0.37
11. G., 45 ‘( M.. 0.46 0.42 0.38 0.26 0.46
A. I>., 20 tL F.. 0.32, 0.16
n4.s., 59 (L ill.. 0.58 0.37
c. II. 23 (( (‘ 0.28 0.16 0.16 0.14
E,. G.; 22 ” “:::::::::::::::: 0.84 0.66 0.68
a. B., 38 ‘( F.. 0.60 0.40 0.44
E. M., 48 ” “.. 0.73 0.40 0.41
E. H., 36 [[ M.. :/ 0.36 0.23
S. B., 4+ “ ” . 0.84 0.48 0.67
G. W., 26 “ “ . 0.77 0.49 0.22
IL K., 10 ‘( F., . 0.27 0.23 0.24
R. s., 51 jL ‘[.. ! 0.25 0.32 0.24 0.28
I-

ketoncmia rapidly and consistent,ly decrcas:cld after glucose feeding until,


in 4 hours, it dropped from the initial 38.1 mg. per cent to the near nortnal
level of 1.9 mg. per cent. The response in Case 6 was different. IWO-
nemia declined during the first 3 hours much in the same manner as in t’he
preceding case, but) in the 4th hour it has increased from 2.5 mg. per cent
to 10.8 mg. per cent., an increment of 332 per cent,. As may he noted, this
change coincided with a tlrop of the blood suga.r to a rat,hcr low hype-
glycemic level.
We offer the following interpretation of the facts described. The initial
decrease in kctonemia is due to the fat- and protein-sparing effect of carbo-
M. SOMOGYI 577

hydrate in the metabolism of the liver, the organ which is the source of the
ketone bodies that appear in the blood. Our findings show the existence
of the same process in the intact, normal organism that Edson (2) observed
in liver slices, namely the liver cells oxidize preferentially carbohydrate,
so that when these are available in abundance, the oxidation of fats is
suppressed and, as a consequence, the production of ketone bodies dim-
inishes.

TABLE 11

Showing That IIypoglycemia (Entailed by Alimentary Ilyperglycemia) Elicits an


Increase in Ketonemia

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Case 1 Case 2
-
Blood sugar 1 Blood ketones Blood sugar Blood ketones
I- .I.
hn. mg. per cent mg. per cent mg. per cent ntg. per cent
0 68 0.73 78 0.52
1 172 0.41 123 0.56
2 131 0.40 106 0.45
3 50 47
4 49 1.49 69 1.66

Case 3 Case 4

74 0.39 83 0.36
174 0.47 161
78 146 0.23
6Q 37 0.32
66 69 0.65
67 2.32 81 3.26

Case 5 Case 6
-1-
61 38.1 57 44.3
180 15.8 239 23.5
186 2.8 207 5.5
155 2.1 98 2.5
138 1.9 49 10.8

As to the second change, namely the increase in ketonemia after glucose


feeding, it occurs, as pointed out before, only when the initial alimentary
hyperglycemia entails a transitory hypoglycemic period. This hypogly-
cemia exerts upon ketonemia the same effect as spontaneous hypoglycemia
(3), or the protracted hypoglycemia that is produced by the injection of
insulin (41, and we ascribe it to the same causitive factor; i.e., an increase
in the rate of hepatic glycogenolysis. The greater this increase, the
578 EFFECTS OF GLUCOSE ON KETONEMIA

greater is the rise in the ketonemic level. In support of this view we point
to Case 4 in Table II, in which the hypoglycemia was more intensive
than in the other three examples, and it soon was followed by a substantial
increase of the blood sugar. After 4 hours had elapsed since the adminis-
tration of glucose, this increment in the glucose content of the blood can
be accounted for only by hepatic glycogenolysis. From a comparison of
the blood sugar changes in Cases 1, 2, 3, and 4, it is evident that the in-
crease in the rate of hepatic glycogenolysis was distinctly higher in Case 4
than in Cases 1, 2, and 3. Concurrently, the increase in ketonemia also
was greater; it represents an elevation of 803 per cent above the post-
absorptive, and of 1300 per cent above the lowest (2 hour) ketonemic
level.

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It is generally assumed that the production of ketone bodies is increased
only when the glycogen stores of the liver have suffered a far reaching
depletion. Such a condition can be safely ruled out in our cases in which
normally nourished individuals had consumed 100 gm. of glucose only 4
or 5 hours before the ketonemic level has shown a marked rise. It may be
stated, as was pointed out in a previous study in hyperpyrexia (5), that
an increase in the rate of hepatic glycogenolysis alone seems to suffice to
increase the rate of ketone body production, notwithstanding the amount
of glycogen present in the liver. This interpretation of our findings is
strengthened by the work of Hubbard and Wright (6) who observed a rise
in ketonemia after the administration of small doses of adrenalin to nor-
mally nourished men, directly after a meal.
Indirect evidence in favor of our view is furnished by experiments which
show that ketogenic factors fail to act as such if their glycogenolytic effect
is counteracted. Hirschhorn and Pollak (7) found this to be the case in
the instance of adrenalin. They reported in 1927 that the ketonuria of
phlorhizinized rabbits was markedly increased by the injection of adrenalin;
but the simultaneous injection of ergotoxine, a drug known to block in the
liver the glycogenolytic effect of adrenalin, also prevented its ketogenic
action. Mirsky (8) made similar observations when he used anterior
pituitary lobe extract as the glycogenolytic-ketogenic fact.or. Fasted
rabbits developed considerable degrees of ketosis when injected with the
extract; but the simult,aneous injection of ergotamine or of insulin, both of
which inhibit hepatic glycogenolysis, nullified the ketogenic effect. A
third observation to the same effect was made in this laboratory, under
entirely different conditions. We have shown that the consistent keto-
genie effect of artificial fever, which follows the increase in the rate of
hepatic glycogenolysis, can be completely prevented by continuous injec-
tions of glucose at a rate that suffices to maintain hyperglycemic states (5).
Hyperglycemia, as is known, depresses hepatic glycogenolysis.
M. SOMOGYI 579

SUMMARY

In healthy individuals a measurable decrease of the ketonemic level takes


place within from 1 to 3 hours after the administration of glucose. This
change is attributed to the fat- and protein-sparing effect of carbohydrate
in the metabolism of the liver.
In cases in which the alimentary hyperglycemia is followed by hypo-
glycemia (usually during the 3rd or 4th hour after the administration of
glucose) the ketonemic level rises considerably above the postabsorptive
level; this rise lags behind the appearance of hypoglycemia and occurs in
the 4th or 5th hour, sometimes only in the 6th hour. The explanation is
offered that an increase in the rate of hepatic glycogenolysis entails an
increase in the rate of production of ketone bodies, regardless of the nature

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of the glycogenolytic factor. Thus, spontaneous hypoglycemia, protracted
hypoglycemia caused by insulin, fever, adrenalin, anterior pituitary extract,
all produce increased ketonemia at the same time that they enhance the
rate of hepatic glycogenolysis. They fail, however, to increase ketcsis if,
simultaneously with them, factors are at work which inhibit hepatic
glycogenolysis.
BIBLIOGRAPHY

1. Weichselbaum, T. E., and Somogyi, M., J. Biol. Chem., 140, 5 (1941).


2. Edson, N. L., Biochem. J., 30, 1862 (1936).
3. Somogyi, M., Proc. Sot. Exp. Biol. and Med., 46, 644 (1940).
4. Somogyi, M., J. Biol. Chem., 141, 219 (1941).
5. Somogyi, M., and Kirstein, M. B., Proc. Sot. Exp. Biol. and Med., 46, 640 (1940).
6. Hubbard, R. S., and Wright, F. R., J. Biol. Chem., 49, 385 (1921).
7. Hirschhorn, S., and Pollak, L., 2. klin. Med., 106, 371 (1927).
8. Mirsky, I. A., Am. J. Physiol., 116, 322 (1936).
EFFECTS OF GLUCOSE FEEDING
UPON THE KETONEMIA IN HEALTHY
MAN
Michael Somogyi
J. Biol. Chem. 1942, 145:575-579.

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