Acts Medicn Scandinnvicn. Vol. CL, fasc. I, 1954.

From Medicinsk Afcleling, Blegdamshospitalet, Copenhagen (Chief Physician: N. R. Krarup, M. D.).

Ketone Metnbolism in Obesity 11.’ BY

AAGE WARMING-LARSEN.

(Submitted for publication March 18, 1954.)

In obesity in mail the degree of ketonemia during starvation has been dem- onstrated to be liable to wide variations in comparison with normal controls

In a previous paper (9) the results of fasting experiments in 16 obese persons have been presented. The number of obese patients showing starvation ketonemia of very high or very low degree was found to be strikingly high. The total num- ber of obese patients, however, was too small to demonstrate any significance of the findings. The investigations have therefore been continued, and in the present paper the findings in a total number of 42 obese patients (including the 16 pa- t,ients already mentioned) are reported. As control group there have been used the same 25 normal persons as before.

(1, 2 , 3, 4, 6, 9).

Technique nnd experimental procedure.

All the patients have been examined in the same way during one or more fasting periods of 3 days. They were confined to bed during the experiments and the blood ketone concent,ration was determined regularly, finally in the morning of the fourth day. Analyses of ketone bodies were performed by the micromethod of Jacob Poulsen (7) with separate determination of 8-hydroxybutyric acid and acetoacetic acid + acetone (7, 8). All the patients received a standard diet for three days before the starvation experiments. In this diet fat, carbohydrate and protein were in fairly constant proportion - a t least not varying, sufficiently to govern, during this short initial period, the degree of ketonemia eventually devel- oping during the fasting experiments.

l The studies here reported have been carried out by the aid of a grant from P. Carl Peter- sen’s fond.

48

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Fig. 1.

In 24 patients the starvation experiments were repeated after a week (2 or 3 times). Between the fasting periods the patients received various low caloric diets (800 cal. or 1,600 cal.) t o ascertain if this variation would exert any influence upon the degree of starvation ketonemia (vide infra).

All details concerning technique and experimental procedure have been de- scribed before (8, 9, 10).

Resulte. In the 42 obese patients the blood ketone concentrations at the beginning of the

fasting experiments did not differ from the values determined in the 25 normal persons in the control group (9, 10).

In both groups gradually increasing blood ketone concentrations were found during the first 3 days of starvation: whereafter the values remain fairly constant.

Using the blood ketone concentrations found in the morning of the 4th day for comparison of the degree of starvation ketonemia in the two groups the following results have been found (fig. 1):

The blood ketones are expressed as /I-hydroxybutyric acid, but include all three compounds. Where more than one fasting experiment has been performed in the same patient, only the first result is presented. In the cases where the starvation experiments have been repeated, somewhat lower values have been demonstrated in the second or third experiment with some of the patients in whom the degree of starvation ketosis in the first experiment was high, but the differences were not great.

When the starvation experiments were repeated, it was found that the results were not significantly different in the second experiment with a 1,600 cal. diet

KETONE METABOLISM IN OBESITY 11. 49

as compared with a 800 cal. diet in the week between the two fasting periods. This finding was the same in patients with high and low degrees of fasting ketosis.

To make the survey of the results easier, the patients have been divided into three groups, using the blood ketone concentration found in the morning of the fourth day of the first fasting experiment:

Group I: 0-10 mgyo 8-hydroxybutyric acid Group 11: 11-30 mg% )) 0

Group 111: > 30 mg% ))

It must be admitted that this division is somewhat artificial. Group I , how- ever, comprises patients having such a slight degree of fasting ketosis as is very seldom found in normal persons, and besides i t has been demonstrated that the amounts excreted in the urine of these patients are so small that even the nitro- prusside test will be negative or only slightly positive in the urine. The ferric chloride test will always be negative in the urine of patients belonging to group I, as has been discussed before (8, 9, 10). Group I I I comprises patients with a fasting ketosis after 3 days higher than 30 mg% - a concentration that is very seldom exceeded by normal persons. Clinical symptoms of ketosis are normally not seen in patients having a blood ketone concentration less than 30 mg%.

The results of this grouping of normal persons and obese patients have already been demonstrated - for only the first 16 obese patients (9, 10).

In fig. 2 a total number of 42 obese patients (including the first 16) are re- presented. (As mentioned above only the results of the first fasting experiment in each patient is demonstrated.)

I n the group of normal controls 18 persons out of 25 (72 %) belong to group I I (11-30 nig%). Only 2 (8 %) belong to group I (0-10 mg%) and 5 normal persons (20 %) exceed a blood ketone concentration of 30 mg% (group I I I ) .

Of the 42 obese patients no less than 28.6 % (12 patients) developed a blood ketone concentration of under 10 mgyo /3-hydroxybutyric acid, and in 35.7 yo (15 patients) the ketonemia a t the end of the first fasting experiment of 3 days was found higher than 30 mg% P-hydroxybutyric acid.

I n no case did patients belonging to group I1 or I11 show degrees of fasting ketonemia less than 10 mgyo P-hydroxybutyric acid during repeated fasting ex- periments.

Discussion. These experiments seem to confirm that the inanition ketonemia in obese patients

is liable to much wider variations than in normal persons. This is in good agreement with the findings of other authors in smaller num-

bers of patients (1 , 2 , 3, 4, 6) and with our own results in a group of 16 obese pa- tients (9, 10).

The great number of patients here examined seems to give good evidence that the difference between obese and normal persons concerning starvation ketonemia may be significant.

AAOE WARMINO-LARSEN.

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Fig. 2.

It is not possible to give any explanation of this ))disturbance in ketone metab- olism)) in obese patients. It has been suggested by MacKay & Sherrill (4), and later by Warming-Larsen (9, lo), that the abnormally low blood ketone con- centrations frequently found in starved obese patients may be due to some ))endo- crine disturbance)) of unknown type, whereas the group with very high starvation ketosis was supposed simply to be ))over-eatersv in whom there was marked keton- emia before starvation, providing enough oxidative products to the peripheral tissues to balance the high calorie intake.

A survey of the theories hitherto presented has been given previously in a paper in this journal to which reference is made (9).

Here only a few facts may be pointed out in an attempt to distinguish between what we know and what we believe concerning the fat metabolism of obese persons and the existence of a simple and an $endocrine)) obesity.

1) The blood ketone concentration in obese patients under normal circum- stances (i. e. on a normal diet) is the same as in normal persons (10).

2) The mobilization of fats during starvation is normal, and the slight hyper- lipemia seen in starving obese patients is of the same degree as in non-obese per- sons (9, 10).

3) The rapidity with which the starvation ketosis reaches its maximum (and plateau) is the same as in normal persons, which indicates that there is no dif- ference in the glycogen stores (and their mobilization) as the protein metabolism seems undisturbed in obese patients (10).

KETONE METABOLISM IN OBESITY 11. 51

Whereas the obese patients showing high or intermediate degrees of inanition ketonemia under the circumstances here mentioned do not present any specific metabolic problem, there may still be some doubt whether or not the obese pa- tients with ofailingo starvation ketosis suffer from some ))endocrine disturbance)). As their protein- and glycogen metabolism is normal, their combustion of fats (quantitatively) must be practically normal (as also their mobilization of fats from the depots).

It is suggested that the production of ketone bodies in such patients is dimin- ished, fat combustion possibly following alternative pathways (carbohydrate? low molecular acids?) to a greater extent than normally.

Much work has to be done before we know if there is an endocrine disturbance ( e . g. a greater glucose formation from fats than normally) disposing perhaps to diabetes mellitus. It might be interesting to see if the group of poor ketone formers among the obese patients represent the main part of the diabetics among the obese patients.

It must be pointed out, that even if i t has not been possible in these experiments to demonstrate any influence of the diet in the fore-period on the degree of fasting ketonemia in obese patients, there may be some adaptability to high-fat diets. For practical reasons the fore-periods have been rather short, and especially i t has not been possible to keep the patients on a high-fat diet for a longer pei-iod, as they were admitted to the hospital on account of their overweight. Some evidence has already been given that, for example, the Eskimo race is adapted to a diet high in fats and almost carbohydrate-free, as they are reported to show no keton- uria (5). There is no reason a t all to suppose that the Eskimo race can retain ketone bodies (by aid of the kidneys) to a higher degree than other human beings.

Thus i t cannot be excluded that the significant difference between normal and obese persons concerning starvation ketosis may be due to differences in the diet during a long period before the hospital admission.

Summary.

In 42 obese and 25 normal persons the degree of inanition ketosis was deter- mined. The obese patients showed significantly wider variations than the normals, which is in good agreement with the findings of other authors in small numbers of patients. Especially the group of obese patients witb failing starvation ketosis represents a metabolic problem, and i t is discussed whether they represent a possible ))endocrine)) group (incipient diabetes mellitus patients) or simply a fat- adapted group like the Eskinio race.

It has not been possible in these investigations to give any definite proof of any endocrine disturbance in the obese patients.

52 AAGE WARMING-LARSEN.

Literature.

1. Deuel, H. J. jr. & Gulick, M.: J. Biol. Chem. 1932, 96: 25. - 2. Folin, 0. & Denis, W.: J. Biol. Chem. 1915, 21: 183. - 3. Lauter, S. & Neuenschwander-Lemmer: Ztschr. f. d. ges. Med. 1936, 99: 745. - 4. MacKay, E. M. & Sherrill, J. W.: Endocrinology 1937, 21: 677. - 5. Mitchell, P. H.: A Textbook Of Biochemistry, London 1946: 423. - 6. von Noorden, C.: Handb. d. Path. d. Stoffwechs., Berlin 1907, 2: 207. - 7. Poulsen, J. E.: Studies on the ketosis in diabetes mellitus, Dissert., Copenhagen 1941. - 8. Warming- Larsen, Aa.: Scand. J. Clin. & Lab. Invest. 1949, 1: 245. - 9. Warming-Larsen, Aa.: Acta Med. Scand. 1948, Suppl. 206: 424. - 10. Warming-Larsen, Aa.: Nogle kliniske Undersegelser over Ketonstofskiftet, Dissert., Copenhagen 1947.