Formation of Glycogen aftertaking Different Varieties

of Sugar.

AN ABSTRACT,

BY

GRAHAM LUSK, Ph. D.,Assistant Professor of Physiology, Yale Medical School,

REPRINTED PROM THE

Heto York J&tfncal Journalfor August 20, 1892.

Reprinted from the New York Medical Journalfor August SO, 1892.

FORMATION OF GLYCOGEN

AFTER TAKING DIFFERENT VARIETIES OF SUGAR.

AN ABSTRACT*

By GRAHAM LUSK, Ph. D.,ASSISTANT PROFESSOR OF PHYSIOLOGY, YALE MEDICAL SCHOOL.

There are two theories regarding the formation of thecurious substance called glycogen, which is found depositedin various organs of the body, and especially in the livercells.

According to one theory, known as the “anhydride theo-ry,” dextrose and those sugars which are changed into dex-trose in the intestinal canal are transformed into the anhy-dride of dextrose or glycogen by the activity of the livercells. This theory arose because large quantities of glyco-

* Ueber die Glyeogenbildung nacb Aufnahme verschiedener Zucker-arten. Nach den Yersuchen der Herrn Dr. Jac. G. Otto aus ChristianiaDr. A. C. Abbott aus Baltimore, Dr. Graham Lusk aus New York, undDr. Fritz Yoit aus Munchen. Zusammengestellt von Carl Yoit. (Ausdem physiologischem Institut zu Miinchen.) Zdtschrift fur Biologie,vol. xxviii, p. 245, 1892.

Also, Ueber die Glycogenbildung bei Aufnahme verschiedener Zucker-arten. Von Graham Lusk. Dissertatio inauguralis. Miinchen, 1892.

Copyright, 189; y. Appleton and Company.

FORMATION OF GLYCOGEN.

gen were always found in tlie liver after feeding dextrose,lajvulose, and cane sugar.

The second theory maintains that the glycogen is de-rived from the continually decomposing albumin. So longas no sugars reach the blood from the intestinal canal, thisglycogen is swept away by the blood current as soon asformed and contributes to fulfill the conditions for combus-tion in the cells. When, however, sugars are introducedinto the blood, they burn in preference to the less easily de-composable glycogen, and hence the glycogen accumulatesin the organization. The more easily combustible sugarsprotect or “ economize ” the less combustible glycogen.This, then, is the “ economy theory.”

Wollfberg especially showed the economy theory to betrue in certain cases. Experimenting upon hens, he found,on feeding to them a constant amount of carbohydrates wdthvarying amounts of albumin, that the glycogen stored inthe liver increased with the amount of albumin given. Theprincipal proof apparently emanated from Luschinger andothers, who showed that chemically the glycogen was alwaysthe anhydride of dextrose. Maydl asks how a ketone (laevu-lose) can go over into an aldehyde (dextrose).

At one time there was general acceptance of the “ econo-my theory.” Sugar burned most easily, glycogen next, andfat with the greatest difficulty; hence sugar economized theglycogen formed from the decomposition of albumin, whileglycogen burned in advance of the fat. Therefore we seewhy ingestion of the less combustible fat does not affect theamount of glycogen stored.

In the students’ exercises held by Professor Yoit, it hasbeen customary to feed rabbits, which had been starved sev-

eral days, with a large quantity of sugar (sixty grammes ofcane sugar in solution), and, after eight hours, to kill the.rabbits and demonstrate the glycogen in the liver. The

FORMATION OF GLYCOGEN. 3

amounts found varied from four to nine grammes, and ranas high as twelve per cent, of the fresh, or forty per cent,of the dry, substance of the liver.

The possibility of producing so large a quantity of gly-cogen in so short a time brought up the question whetherthis large amount could have been produced from the de-composition of albumin during the same eight hours. ErwinYoit fed a goose for five days on rice, and the amount ofglycogen found in the liver at the end of the experimentproved to he three times greater than what could possiblyhave been derived from the albuminoid decomposition ofthe whole five days. Some of the ingested carbohydratesmust have been changed directty into glycogen. Here wehave a proof of the anhydride theory, but by no means arefutation of the economy theory. Indeed, Kiilz has indis-putably shown that glycogen could be produced from albu-min. We see, therefore, that the ingested carbohydratesfirst “ economize ” the glycogen produced from albumin,and afterward, when present in large quantities, are them-selves directly changed into glycogen by a process of dehy-dration. The truth of both theories, then, seems to be es-tablished.

These facts cause us to consider (l) what kinds of sugarare directly convertible into glycogen, (2) what kinds merely“ economize ” the albuminoid glycogen, and (3) why it isthat one and the same glycogen is always produced, evenafter the ingestion of the most varied kinds of sugar. Pro-fessor Yoit therefore instituted feeding-experiments withdextrose, cane sugar, maltose, laevulose, milk sugar, and ga-lactose. The animals fed were rabbits and fowls. Theywere starved from four to six days, when the amount ofglycogen in the organization seldom exceeds unweighahletraces. Then, eight hours after ingestion of the sugar solu-tion, the animal was killed and the liver treated for analysis.

4 FORMATION OF GLYCOGEN.

Experiments made by various authors show that in astarving rabbit the amount of glycogen possibly obtainablefrom eight hours’ decomposition of albumin can not exceed0’66 to T52 gramme; in the case of fowls, OT9 to 2*29grammes. Amounts of glycogen, therefore, which do notoverstep these limits can be attributed to the albumin andnot to an ingested material.

The following table shows the amounts of glycogen wefound after ingestion of the various sugars named :

A review of the above table demonstrates indisputablythat large doses of galactose and milk sugar bear an entirelydifferent relation to the formation of glycogen to that ex-hibited by dextrose, cane sugar, laevulose, and maltose. Thelatter four produce glycogen in large amounts, whereas theamount produced after feeding with milk sugar and galac-

Kind of Sugar.Weight ofglycogenin liver.

Per cent, ofglycogenin liver.

50 grammes dextrose, fowl (Otto) 5-37 • 7'3 15 3 tielb80 “ “ rabbit (Otto) 9-27 16-860 U cane sugar, fowl (Otto) 4-94^ 13-3 )55 u “ rabbit (Otto)... 4-35 . 5 • 5 7-4 M060 u “ “ (Otto)... 8 • 50 12-0 (

30 u “ “ (Lusk)... 4-06 6 ■ 554 8 “ laevulose, fowl (Otto) 3-99 10-5 1054 8 “ “ rabbit (Otto) 5-27 9-1

:

60 u maltose, fowl (Otto) 4-07 A • 1 10-4 1 o

60 u “ rabbit (Otto) 4-13 8-1 155 u galactose, fowl (Otto) 0-67 0 - 8 1-3 .1J68 2 “ “ rabbit (Otto).... 0-87 1-532 u milk sugar, fowl (Otto) 0-12) 0'2 ) 148 u “ rabbit (Otto)... 0-87 1-732 u “ “ (Otto).., 0-14 0-4

u “ “ (Otto)... L 0*8 0-950 a “ “ (Abbott). 0-750 u “ “ (Abbott). 1-250 u “ “ (Abbott). 1.550 a “ “ (Lusk)... 2-18 J 3.6 J

FORMATION OF GLYCOGEN. 5

tose is so small as to be derivable from the decompositionof albumin. Not only our investigations, but likewise thoseof Kiilz, confirm these same relations.

How, then, are we to explain the large quantity of gly-cogen found after feeding dextrose, cane sugar, laevulose,and maltose ? Perhaps the last-named three are trans-formed into dextrose in the intestinal canal. It has longbeen known that large quantities of sugar ingested producean excretion of sugar in the urine, and from the variety ofsugar excreted we may form some idea of what has goneon in the body. We therefore turn to the consideration ofthe behavior of the different sugars in the intestinal tractand their emission in the urine.

Cane sugar certainly is transformed, in part, into dextrose.Professor Yoit has for thirty years shown in his lectures that ao’3-per-cent. hydrochloric-acid solution at the body tempera-ture quickly changes cane sugar into a mixture of Itevulose anddextrose —i. e., invert sugar. Certain ferments have the sameaction. The writer once gave a rabbit sixty grammes of canesugar and killed the animal six hours afterward. He foundtwenty times more invert sugar than cane sugar present in theintestines. Hence we may conclude that a considerable amountis absorbed as dextrose. Because much cane sugar is found inthe urine, it by no means proves that all the ingested cane sugaris absorbed as such; it could easily be that cane sugar is lessreadily burned, or, one may reason, that perhaps it may not beconverted into glycogen, and in this way be removed from thecirculation. It is probable that the greater part of the canesugar is absorbed as invert sugar, from which the glycogen ismanufactured.

Lcevulose remains unchanged in the intestines, is absorbedas such, and in extreme cases is emitted in the urine (Otto,Fritz Yoit). The Isevulose given was nearly pure, and de-structible by boiling with ten-per-cent, hydrochloric acid. Inthe intestinal contents, and in the urine of the animals experi-

6 FORMATION OF GLYCOGEN.

mented upon, the sugar found was equally so destructibleDextrose would not have been destroyed.

Maltose is, with dextrine, a product of the action of diluteacids on starch paste, which action, if prolonged, yields dextrose.Certain ferments have the power of changing starch into maltoseand dextrine, and then finally into dextrose. The pancreaticand intestinal juices possess this power to a high degree.Maltose, therefore, is transformed into dextrose in the intesti-nal canal.

Galactose is probably absorbed unchanged.Milk sugar , like galactose, produces no large amount of gly-

cogen, and hence it was inferable that it did not break up intoa mixture of dextrose and galactose (into which constituents itcan be converted by treatment with acids). If the decomposi-tion did take place in the intestines, then the dextrose formedmust ferment with yeast, and our investigations are based uponthis fact. Dr. Abbott made the preliminary experiments, and,with great diligence and patient labor, devoted himself to thesolution of the problem. In his experiments he used the or-dinary commercial yeast, and noticed that the solutions ob-tained from the intestines treated with this yeast rapidlydecreased in their percentage of sugar, and after a few days thewhole of the sugar had disappeared. The results were at firstapparently inexplicable, but the cause was the presence offoreign bacteria (probably lactic fermentation). Some monthsafter the unavoidable departure of Dr. Abbott from Munichthe writer took up the subject, using a culture of pureyeast (Saccharomyces apiculatus). The result of the investi-gations was to establish the fact that milk sugar undergoesno change in the intestines, and is emitted unchanged in theurine.

It is evident that cane sugar and maltose form dextrosein the intestinal canal; that laevulose, milk sugar, andprobably also galactose, do not form dextrose, but are ab-sorbed unchanged. But ingestion of hevulose produces alarge store of glycogen in the body. Hence, not only dex-

FORMATION OF GLYCOGEN. 7

trose is converted into glycogen, but Isevulose must alsoundergo the same change.

Now, if cane sugar and maltose form glycogen only invirtue of the fact that the intestines change them into dex-trose, by excluding the factor of the intestinal tract theyshould not produce glycogen. The factor of the intestinaltract could be obviated by subcutaneous injection, in whichway we were able to bring considerable amounts of sugarinto the circulation. Then, again, Isevulose, milk sugar,and galactose, when introduced by subcutaneous injectiondirectly into the tissues of the body, should form glycogenonly in the event that the liver itself has the power to turnthem into dextrose.

These experiments consisted in the subcutaneous injec-tion of the different sugars, and were performed by thewriter upon starving’ rabbits. Fifty grammes of the sugarwas dissolved in water to form 150 c. c. solution, and 10 to15 c. c. were injected at intervals of about an hour for tenhours. The animal was afterward left quietly for fivehours, and then killed. The average of glycogen obtainedis given below; in each case two or more experiments weremade :

This table, showing results after the subcutaneous in-jection of the various sugars, exhibits very striking dif-ferences. It is evident that dextrose produces much gly-cogen, and cane sugar little. Hence the large amount ofglycogen found after cane sugar has been taken into the in-

Grammes of glyco-gen in liver.

Per cent, of glyco-gen in liver.

50 Grammes dextrose 3-5 5-055

“

“ cane sugar 0-4 0-750 “ laevulose 5-5 5-950 “ milk sugar 0-3 0-8

8 FORMATION OF GLYCOGEN.

testines is in virtue of its change there into invert sugar—-i. e., a mixture of dextrose and laevulose. Maltose probablyacts like cane sugar. Milk sugar shows little increase inthe glycogen stored, and therefore can not be converted intodextrose. On the contrary, large quantities of glycogen,even as high as 9*l per cent., were found after subcutaneousinjection of hevulose. There can be but one conclusion,therefore, and that is that the liver cells have the propertyof transforming laevulose either into dextrose, or directlyinto the anhydride of dextrose, glycogen. Emil Fischershowed a few years ago that dextrose could he made fromIfevulose in the laboratory. This is now seen to have itscounterpart in the animal kingdom. Entirely analogous tothis is the preparation of milk sugar from dextrose in theglands of the breast.

It is remarkable that only the two fermentable sugars,dextrose and lamilose, are convertible into glycogen. Theliver cells manufacture glycogen from these two sugarsonly.

In plants there are similar transformations. ArthurMayer, working in Gottingen, has shown that leavesmake starch of dextrose, of laevulose, and galactose. Alsovegetable starch is made from mannite, dulcite, andmaltose.

The importance of glycogen for the animal organizationis that of a transitory, reserve material.

There is usually taken, at an ordinary meal, an excessof albumin, fat, and carbohydrates, over and above the im-mediate needs of the body. This excess must not remainin the blood, as there it would disturb the processes in thecells, or it would he excreted in the urine. The cells arenot able to decompose this excess in a short time, and evenif this were possible, more energy would thus be liberatedthan necessary for the needs of the body in the time given-

FORMATION OF GLYCOGEN. 9

To obviate these disturbances, the excess is deposited in aless combustible form and in a less readily accessible place.The soluble circulating albumin of the blood is, to someextent, deposited as systemic albumin in the substance ofthe body; the fat is deposited in the fatty tissue, and thesugar is deposited in various organs of the body, especiallyin the liver cells, as the less diffusible, less decomposableglycogen.

We know that the facts go to prove that albumin isbroken up in the body into a nitrogenous portion and a

non-nitrogenous portion. The investigations of Federshow that in a dog the greater part of the nitrogenous por-tion of the albumin consumed is already excreted in thefirst fourteen hours, while the non-nitrogenous portion re-quires twenty-four hours for its combustion. This first de-composition of albumin into a nitrogenous and a non-nitro-genous portion is not accompanied by the liberation ofmuch energy, as, in the few hours of this decomposition,more energy would be set free than needed. The principalsource of energy comes, therefore, from the non-nitrogenousportion, just as it is also found in the non-nitrogenous sugarand fat. The temporary excess of the non-nitrogenous por-tion of the albumin, as well as the excess of food sugarand fat, are deposited in the body as fat and glycogen, andthen, in the course of twenty-four hours, gradually re-enterthe blood current and are burned in the cells. In this waythe glycogen produced is always swept away again inamounts dependent upon the needs of the cells.

The first demonstration of glycogen by Claude Bernardwas little more than play with an interesting toy. Experi-ments since have shown that the transformation of theeasily combustible sugars into the less combustible glyco-gen is at once one of the most wonderful and one of themost important arrangements in the animal organization.

10 FORMATION OF GLYCOGEN.

In closing this article, and in furnishing the Americanprofession with the principal results of these latest viewsand investigations of Professor Voit, the writer takes theopportunity to express his deep gratitude to his greatteacher, and his high personal admiration for him devel-oped during long contact in the laboratory.

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