520 Editor: M. WINITZ 
SELMA SNYDERMAN was doing some work on amino acids some years ago, and she was studying 
the requirement of leucine. She found that as leucine was withdrawn without any other change in 
the diet the level of isoleucine in the blood rose. This is a phenomenon that is now known, and 
I think it is a thing that might well be studied further. I would like to go just one step further, 
and make the point that there is a connection, possibly in an indirect way, with certain forms of 
hypoglycemia, whereby blood glucose has been altered in these cases by high protein, and espe- 
cially by high leucine level in the diet, and this in turn, it is felt, is also connected with the altera- 
tions in the secretion of certain enzymes. 
Winitz: May I add a comment concerning the relation of leucine to hypoglycemia. Some 
years ago, we studied the effect of toxic doses of the essential amino acids on blood sugar, liver 
glycogen and muscle glycogen levels. Each of the essential amino acids, as a single LDgy., dose, 
was injected intraperitoneally into the rat and blood samples were withdrawn periodically by 
way of the caudal vein until the animal died. It was found that those animals treated with L- 
leucine, L-isoleucine, L-phenylalanine or L-tryptophane all died with a very marked hypoglycemia. 
A determination of the liver glycogen and muscle glycogen levels of the animals revealed a 25- 
to 100-fold decrease in these levels as compared to controls. That there was no apparent relation- 
ship between the toxicity of amino acids and the effect of these compounds on the blood sugar 
level was subsequently revealed by the fact that although the simultaneous administration of 
glucose did not alter the lethal effect of these amino acids, the animals now died with a marked 
hyperglycemia. It therefore appeared that the animals were not dying as a result of the hypo- 
glycemia per se. 
We have also carried out some studies with dietary leucine—isoleucine imbalances. The initial 
studies in this area were, of course, carried out by ELVEHJEM, HARPER and their associates, who 
found that a dietary balance between leucine and isoleucine is necessary for optimal growth. The 
ideal dietary ratio of these amino acids, in our own experience with chemically defined diets, 
appears to be in the vicinity of about ro parts of leucine to 6 or 7 parts of isoleucine. If you go 
too far beyond these values in either direction, then a imbalance develops which is reflected in 
poorer dietary intake and consequently in poorer growth of the animals. Thus, for example, it 
is not necessary to withdraw a certain amount of either leucine or isoleucine from completely 
adequate diets in order to get poorer growth but merely to add one or the other of these com- 
ponents to the diet in an amount sufficiently large to disturb the ratio. 
What is not generally realized, either, is that there is a delicate balance, not only between 
leucine and isoleucine, and perhaps valine enters the picture here too, but between lysine and 
tryptophane as well. It appears that the most efficient dietary ratio of lysine to tryptophane is 
about 6 or 7 to I on a molar ratio basis. 
SCHREIER: I should like to make an addition to the remarks that Dr. Wi1NniITz just made. In the 
recent medical literature one can find that leucine increases the excretion of insulin—PAYNE 
and others did a determination of insulin in blood and claimed to have found very high in- 
creases—let’s say “eine Ausschwemmung.” 
The lysine-tryptophane imbalance has been stressed very much among the classical nutritionists. 
ALBANESE Claimed that lysine and tryptophane should have, in human nutrition, a certain 
ratio, and he published several papers where he put in the value of the protein according to the 
tryptophane-lysine content. The nutritionists believe, and I believe it too, of course, that 
lysine is the amino acid which is needed most in growth because all the proteins of the different 
cereals, wheat and so on, are very poor in lysine; this amino acid is very important for the de- 
veloping countries. Of course, some big firms wanted to sell their tons of lysine, and they proposed 
that lysine be added to flour and to different foods in the U.S.A. and in western Europe. We 
became interested to determine whether lysine had any toxic effect and whether it was meaning- 
ful to add lysine or whether it was much better to add some cheap protein to the diet. So we carried 
out some studies on infants and on rats. If we increased the lysine content of the food by adding 
700 mg/kg body weight to the milk formula as ALBANESE has suggested, then we got not only a 
higher excretion of lysine but of many another amino acids too. We tried to show the same thing 
in rats with high doses of lysine, and we could produce in this way a permanent hyperamino- 
aciduria. 
WInItz: Some of our own experiences have led us to the belief that the degree of essentiality of 
lysine as a dietary component—for that matter of any of the so-called essential amino acids—is 
dependent to a large extent on the clinical state of the animal. In the case of rats bearing the 
WALKER tumor, lysine appears, ironically, to be one of the least essential of the essential amino 
acids. We made this somewhat bizarre observation some years ago when we force fed various 
chemically defined diets to rats bearing the WALKER tumor as well as to normal controls. These 
diets differed from one another in that, although they all incorporated nine of the ten essential 
amino acids, each lacked a different one; they were otherwise identical and contained all of the 
necessary dietary components. Diets which were devoid of one of the branched-chain amino 
acids, valine, isoleucine or leucine, led to the most toxic effects. The valine-free diets induced 
References p. 524 
