NUTRITION PROCESSES IN THE TISSUES OF THE BODY - while it is probable that the liver modifies the recently-digested raw material of food before it reaches the common stock of the blood, it is quite unknown what (or, indeed, if any) difference exists between the action of the liver on blood laden with raw material immediately after a meal and its action on blood traversing its capillaries during a fast. Does the liver exert an action on recently-imported fat, peptones, and sugar in any sense different from the action it exerts on fatty, albuminous, and sugary matters as they exist in the common stock of blood 1 Or - which is the same question - do the fats, albuminous matters, and sugars of the portal blood differ at all from the fats, albuminous matters, and sugars of ordinary blood 1 While this question remains unanswered it will be well to consider the liver as like any other tissue drawing on the common source of nutriment, the blood, for its own particular purposes, and not as an organ akin to the special digestive organs, devoted to the elaboration of food for the benefit of the other tissues.

It need not be so, however, with the lymphatic structures with which the chyle of the lacteals comes into contact before it is poured into the blood. Chyle from the thoracic duct at its entrance into the veins is of course mixed with the general lymph of the body, - the juice of the tissues which is collected in the lymph- vessels and carried back to the blood. It is a milky fluid which coagulates on standing, the clot of which after some time becomes tinted red at the surface from the presence of immature red corpuscles. The coagulum consists of fibrin resembling that of the blood. Other constituents of chyle are white corpuscles, oil-globules coated with albuminous matter, i.e., emulsified, and exceedingly fine fatty granules usually spoken of as the "molecular basis of chyle." Chyle obtained from vessels nearer the intestines has very little fibrin, very few white corpuscles, and no red corpuscles, It is probable, therefore, that the raw matters of digested food are undergoing a process of manufacture into blood during their passage through the lymphatic glands to reach the thoracic duct.

When once they arrive at the blood, the imported materials of food are lost beyond our power to follow them individually. The question now becomes one of the interchanges between the blood generally and the tissues. That such an interchange occurs there can be no doubt ; for if all food be withheld from an animal the tissues rapidly grow less in quantity, while the blood maintains a fairly constant composition. If such an animal bo fed, the tissues regain their former weight, and may even store up an overplus of matters, while again the blood remains of of proximately constant composition. The tissues can both take away from the blood and give to the blood such matters as are necessary. But the matters taken from the blood are not in the same form as the matters given up to the blood. When blood is made to circulate through living tissues of whatever kind the blood entering the tissue always has a different composition from the blood which leaves it. The tissues, therefore, are laboratories in which materials abstracted from the blood are transformed. To these chemical operations of transformation which occur in living tissues the term " metabolic " has been applied, a term first used by Schwann, and happily reintroduced by Michael Foster.

What now becomes of the products of the metabolic activity of the tissues 2 We have hitherto considered the tissues as taking matter from the blood, changing the form of it, and giving it back to the blood ; but this is far from being the true account of the process. It does indeed represent all that we know of the metabolism of many tissues. In muscle, for example, matters are drawn from the blood, converted to other shapes within the tissue, and sooner or later cast out into the blood-current again. The same may be said of nerve-tissue and possibly of some other tissues. In secreting glands the case is different. Seine only of the products of tissue-metabolism are returned to the blood ; others are poured into the ducts of the glands as the glandular secretion, and so leave the body altogether. This happens, for example, in the digestive glands, the milk-glands, and the kidneys. In a third order of tissues the case is different again, for here some of the products of metabolism may be retained in the tissue for an indefinite time. This occurs in certain tissues which have been called storage tissues, and of which fat is a typical example. Lastly, the liver is a complex organ whose metabolic products are disposed of in all three ways, - part being cast at once into the blood, part being accumulated in the tissue itself as glycogen and passing into the blood at intervals as the body needs it, and a third part being poured into the biliary ducts in order that it may escape into the intestine. It will be well, therefore, to recognize three methods of the disposal of metabolic products, and to classify the tissues accordingly.

Metabolism of Muscular Tissue. - To arrive at a knowledge of the chemico-vital changes occurring in any tissue we must compare the matters entering the tissue with the matters issuing from it. It is only from such a comparison that we can infer the changes which go on within the tissue. In the case of muscle there is yet another method by which we can obtain inferences as to the nature of the metabolic changes. We have reason to believe that the tissue-changes of active muscles are simply the exaggerated form of changes which constantly occur. If we may assume this, a comparison of the chemical composition of muscle before and after a period of activity will help us to a knowledge of the changes that occur irk muscular action, and, by implication, a knowledge alsgrof the common metabolic changes of the tissue. Now a comparison of muscle before and after action shows that during activity the quantity of CO, becomes very largely increased ; at the same time the muscle becomes of acid reaction from the development of lactic acid ; the amount of bodies soluble in water decreases, while the amount of bodies soluble in alcohol increases ; the amount of glycogen decreases, while that of sugar increases ; and, finally, bodies develop which have a strong affinity for oxygen. If we compare the matters entering and issuing from muscular tissue we shall find that muscle gives up much CO, during activity, that the issuing blood is rich in reducing substances, and that it acquires sarcolactic acid. The circumstance of most importance in this comparison is that carbon dioxide is liberated in large amount without the immediate interaction of oxygen ; the CO, is produced from some body in the muscle which already contains within itself the 0 necessary for its formation. The fact of next importaNp is the absence of all indications of a large expenditure of nitrogen. Relying on these discoveries, physiologists have supposed that the metabolic changes of muscle follow some such course as the following. Non-nitrogenous organic material, along with oxygen, is absorbed into the tissue from the blood. In the tissue-cells it is elaborated with nitrogenous matter already in the tissue into a complex body called inogene substance, containing a nitrogenous factor linked to carbon, hydrogen, and oxygen. During the life of the tissue, and to a much greater extent during muscular activity, this inogene substance is split up into a nitrogenous portion and a non-nitrogenous portion, of which the former is retained in the tissue to be again worked up into inogene substance, while the latter is resolved into more stable bodies which escape. The full number of the effete bodies is not at present known to us ; it doubtless includes more than carbon dioxide and sarcolactic acid, but these are the only bodies whose existence has been definitely determined.

.metabolism of Glandular Organs. - Of late years very much light has been shed on the processes of glandular cells, but it has been chiefly on their anatomical aspect. We know very little, indeed, of the nature of the chemical changes going on within the glandular cells, because, although we can ascertain approximately the coin-position of those products of the changes which escape into the glandular duct, we as yet know so little of those products which escape into the blood. We know, however, that mucin is capable of being formed in the interior of epithelial cells out of some non-mucous antecedent. We also have some reason for supposing that the gastric glandular cells - the border-cells - select phosphate of sodium and sodium chloride from the blood, and these bodies have been shown to be capable of interacting in such a way as to yield free hydrochloric acid. In the secretion of milk it is tolerably certain that the fat and the casein are both formed out of proteid matter within the glandular cells. Even the milk-sugar has been thought to be elaborated out of some non-saccharine substance, or even out of some substance that is not a carbohydrate. In the case of the pancreas we know nothing of the actual chemical decompositions that occur, but we do know that they occur in two well-marked stages. In the first a body is formed which is stored in the gland-cells, as the inogene substance is supposed to be stored in muscle ; in the second this body is resolved into other but still complex bodies, of which the trypsin ferment of the secretion is one. Among the glandular organs we may mention the kidney, respecting whose secretive activity it is far from certain that it entirely consists of physical filtration or powers of mere selection. No doubt many of the constituents of urine are simply filtered off from the blood, while others are undoubtedly abstracted owing to some peculiar attraction which the renal cells exert upon them. But there is some reason to think that others may be formed within the kidney-tissues as products of cell-metabolism. As yet we hale no definite knowledge concerning the nature of the metabolic changes.

Metabolism in the Storage Tissues. - Of these the first that we shall describe is adipose tissue or fat. Fat appears to be accumulated in ordinary connective-tissue corpuscles. What metabolic changes occur in connective-tissue corpuscles which are not accumulating fat we do not know ; but under certain conditions of overfeeding the metabolism is so varied that fat is deposited within the cell. At first it appears in the form of fine granules ; these soon coalesce to globules, which afterwards enlarge by the confluence of granules subsequently formed. The exact changes of which this fat is the outcome, or one of the products, are entirely obscure. It is enough if we can establish the probability that fat may be derived from the proteid protoplasmic matter of the fat-cell. We are not here guided, as in the case of muscle, by analysis of the blood approaching the adipose tissue and the blood leavino. it. Nevertheless, there is little doubt that fat may be derived from the proteid elements of food through the activity of living tissue-cells. That proteid matter readily lends itself to a decomposition of which fat is one product is seen in the formation of fat-like " adipocere " in the nitrogenous tissues of dead bodies. which have been for some time buried or immersed in water ; and it is likewise seen in the process of " ripening " in cheese, in which the fat increases while the albuminous matter diminishes. But in addition to these general facts, suggestive though they are, there are not wanting proofs of a more particular kind that fat may result from proteid decompositions. If dogs are fed on starch and fat with no proteid food at all, the carbon stored up in the body can all be accounted for by reference to the fat of the food and the proteid matter of the body which, in the state of starvation, came to be disintegrated. In many other cases it seems clear that the fat stored up by animals during fattening unquestionably comes in part from the nitrogenous matters of food. But a consideration of the relative amount of carbon and nitrogen contained in proteids and in urea, which is the final product of the oxidation of proteid matter, would alone lead us strongly to suspect such an origin of fat. If all its nitrogen reappeared in the form of urea, 300 grains of proteid would give rise to 100 grains of urea. But 100 grains of urea contain but 20 grains of carbon, whereas 300 grains of proteid matter yield 159 grains of carbon. What has become of the deficit of carbon? If it has not been burnt off as carbon dioxide, it must remain within the body in Some non-nitrogenous form.

If fat may be derived from proteids in the body, it is now equally certain that in some animals at least fat may come from carbohydrates of the food. Lawes and Gilbert have conclusively shown that as much as 40 per cent. of the stored-up fat in well-fattened pigs could not possibly have come from the nitrogenous parts of the food, and that it must have been derived from the carbohydrates.

All these facts render it very probable that the fat-forming tissues pick out from the blood albuminous or non-nitrogenous matter, transform it, retain the fatty element and discharge the rest. But it must not be forgotten that fat of food may, on finding itself in the blood, be taken up by appropriate tissue-cells and stored up without undergoing further change. Even this, although it seems so probable, may not at once be assumed to occur in such a simple manner. It is true that, if an animal be fed on fat resemblinc,c' the fat of its own tissues, it might be assumed that the fat which it stores is simply absorbed by the tissue-corpuscles as an amoeba absorbs its food. But if this were really the manner of the process we should expect that allied fats substituted for the natural fat would be equally well taken up and stored, This, however, is not at all the case. Dogs fed on a mixture of palmitin and olein, but no stearin, are found on analysis to have stearin in their body-fat ; just as dogs fed on palmitin and stearin, but no olein, are found to have an abundance of olein stored up. And, even when fed on spermaceti, a dog was found to present mere traces of it in the fat accumulated in its tissues during the experiment. In short, all facts go to show that the accumulation of fat does not take place without some display of formative or transformative energy.

The last tissue whose metabolism we shall discuss is the hepatic tissue of the liver. Hitherto we have considered the liver as a digestive gland secreting the bile for the purposes of digestion ; but the liver has other functions which overshadow entirely its function as a digestive organ.

of the liver as altogether independent of one another, vein and hepatic artery, and elaborates these constituents order remain in store within the substance of the liver.

development of physiology, been studied independently of one another for the most part.

If an animal be richly fed on starchy or saccharine food it is found, within a short time of the digestion of the food, that the liver contains a large quantity of a starchy body called glycogen (C6H1005),,. In order to obtain glycogen from liver-substance it is necessary to make use of the tissue of an animal just killed, for the starchy body undergoes an extremely rapid post-mortem conversion into a sugar. Lh'er taken quickly from the still warm body of a rabbit is rapidly divided into small pieces and plunged at once into briskly boiling water. The high temperature prevents the post-mortem change and leaves the glycogen in a condition to be separated. The pieces of liver may then be pounded with sand and water, and the mixture acidulated and filtered. From the filtrate the glycogen may be precipitated by alcohol, and the precipitate may be purified. by boiling in caustic potash and afterwards neutralizing and reprecipitating with alcohol. Or the albuminous matters may be thrown down ''by a solution of mercuric iodide in iodide of potassium before precipitating the glycogen with alcohol. Glycogen so prepared is a white amorphous powder resembling starch inchemical composition ; it is colourless and tasteless. Its aqueous solution is milky, and generally opalescent.

Other tissues and organs besides the liver have been found to contain glycogen. For example, muscles contain some glycogen, which diminishes during muscular activity, while it has been detected in the tissues of embryos and of young animals, as well as in newly-formed pathological growths.

There can be little doubt that glycogen is manufactured mainly out of carbohydrates conveyed to it in the portal vein. If a rabbit be starved for some days, the whole of the glycogen disappears from the liver ; but the store is at once, in the course of a few hours, replenished if starch or sugar of whatever sort (cane, grape, or milk) be introduced into the alimentary canal. The metabolic powers of the liver-cells in respect of glycogen-production are not, however, limited to starches or sugars. If glycerin be injected into the intestines the amount of glycogen in the liver is at once increased. But some preparation of the glycerin is necessary before the liver-cells are able to appropriate it ; and this preparation is accomplished in the true digestive organs, since glycerin introduced into the blood by subcutaneous injection does not bring about any increase in the glycogen of the Ever. Even albuminous bodies, such as fibrin and albumin, freed from all trace of amyloid matter, seem in the case of carnivorous animals to yield glycogen in the laboratory of the hepatic tissue. The same may be said of gelatin. Now it is easy to form a chemical conception of the manner in which such a body as grape-sugar leads to the storing of glycogen, for the dehydration of the sugar would be all the change required for the conversion. But we can at present form no picture of the operation in the case of glycerin and of the albuminous matters ; and the fact that these substances also are amenable to the liver-cells should make us hesitate to assume at once that in the case of sugar the process is the simple one of dehydration. We must wait for further light to be shed upon the interdependence of what we may for the moment call the biliary metabolism and the glycogenic metabolism of liver-cell before we speculate as to the exact nature of the changes.

The liver has, beyond a doubt, the faculty of manufacturing an amyloid body out of various raw matters brought within the range of its activity, and of storing it up for future use. The use to which it is put has been the subject of much speculation and experimental inquiry. The amyloid matter when drawn upon may leave the liver in the form in which it exists there, or it may be converted into some other modification and afterwards transferred to the blood. The fact that other tissues besides the liver contain glycogen, and the fact that some, as muscle, seem to make use of b odycogen in the act of contraction. have been thought to seipportthe hypothesis that the glycogen is conveyed by the blood to their tissues and then consumed. According to this theory the hepatic metabolism ends in the production of glycogen, which merely waits to be cast out into the blood-current at the call of the body generally. Against this hypothesis, as a complete explanation of the use of liver-glycogen, it may be urged that the glycogen of muscle at least disappears on starvation long before the store of glycogen in the liver has been used up. Moreover, the glycogen of muscle is by no means invariably present, and is certainly not indispensable to the activity of the tissue. We may therefore conclude that the use of glycogen by the tissues (when we judge of it by the case of muscle) is not constant enough or important enough to account for the large store of glycogen in the liver. But, if the hepatic glycogen does not leave the liver as such, it must undergo some other change in the liver ; and the circumstance above referred to, that glycogen so readily becomes converted into sugar post modem., at once leads us to inquire whether a similar conversion is not normally effected during life. The inquiry becomes of especial value when we remember that the blood contains a constant proportion of sugar in its composition, which argues such a constancy of supply as could not be due to the direct importation of sugar during the irregular periods of the daily meals. As the amount of sugar in the blood is constant, the periodic introduction of carbohydrate into the organism must be followed by some temporary storing of it in some organ from which it may be constantly, and without intermission, doled out. Now the body contains in many parts the means of the conversion of starches into sugar. The salivary or pancreatic juices with the utmost readiness at the body-temperature change glycogen into a sugar. Many tissues, as well as blood, are said to effect the same conversion, although it is denied that the blood does so unless the blood-corpuscles have been first destroyed. The liver itself, as we have already seen, may bring about the same change, at least after death ; but the activity of the converting substance may be prevented by subjecting it to a temperature of boiling water. If the liver contain the ferment-like body during life, unless its activity be restrained in some way or other, the glycogen which is formed in the liver will be speedily changed into sugar. In regard to the existence of this starch-converting body it is significant that, while it certainly may arise in the blood when the blood-corpuscles are destroyed, the liver is known to be the seat of an extensive destruction of blood-corpuscles. Considerations of this sort, however, are of little cogency ; it would be a strong presumption of the existence of the ferment in question if sugar could be proved to be normally present in the hepatic tissue during life, but the experimental proof of this is beset by great difficulties, and discordant results have been obtained by the different observers. Claude Bernard, to whose researches we owe so much of our knowledge on this interesting question, detected small but perceptible quantities of sugar in quite fresh liver-substance ; but other observers, among whom Dr Pavy is to be reckoned the first, have failed to find even a trace. Further, Bernard was able to make out a decided difference between the amount of sugar contained in the portal vein and the hepatic vein respectively when there was no starch or sugar in the food to load the portal vein. In such circumstances the blood issuing from the liver by the hepatic vein was found to contain a small quantity of sugar in excess of the blood entering the portal vessels. The most accurate and reliable investigations have, however, conclusively proved that this difference does not exist. The matter, therefore, still awaits some crucial test not yet devised. In the meantime we may accept the hypothesis of a conversion of liver-glycogen into soluble sugar as one which, however probable, is not supported by sufficient evidence. Amongst those who have rejected this hypothesis some have had recourse to other assumptions to account for the fate of glycogen in the licsly ; and it has been suggested that glycogen undergoes conversion into fat either in the liver itself or partly there and partly in some other tissue. This suggestion has little direct evidence to support it. It is true that anunals, especially the pig, have the power of storing up fat in their bodies which they cannot have obtained otherwise than from the carbohydraceous constituents of their food. It is also true that the hepatic tissue is often found to contain fat in considerable quantities. But it is easy to see how these facts admit of simple explanation without assuming a conversion of glycogen into fat within the liver-cells. The chemical nature of such a conversion is difficult to imagine ; but it would be rash to assume that the metabolic powers of animal protoplasm are not sufficient to accomplish it.

With regard to the metabolism of liver-tissue which leads to the production of bile we possess but little direct knowledge. The secretion of bile is not a mere act of filtration of already-formed matters from the blood ; but we have at present no conception of the chemical changes which occur in the interior of the liver-cells in the elaborabut also from the resemblance or identity of bilirubin and haematoidin, a body derived from extravasated blood. A large number of facts point very clearly to the conclusions (1) that the liver is an organ in which chemical changes of great magnitude and importance have their seat, (2) that their operation consists in great part in decomposition of proteids.

The high temperature of the blood which leaves the liver, and which is the hottest blood of the body, is the chief proof of the correctness of the first of these conchief seat of proteid metabolism in this organ.

Diabetes. - In connexion with the glycogenic function of the liver it is necessary to refer to a disease which is of special interest to physiologists, from the ease with which the symptoms may be artificially reproduced. The disease itself may be defined as the appearance of large quantities of sugar in the urine, while the total amount of the urine excreted is also increased. Now diabetes of a temporary nature may be produced in animals in a variety of ways. If certain fibres of the medulla oblongata near what is known as the vasomotor centre be divided, as they may be by means of a special instrument, without producing any serious abnormal motor or sensory symptoms, there follows very speedily the excretion of large quantities of sugar in the urine. It is evident that this result is due in some way to an abnormal influence of the nervous system. The path by which the abnormal influence is transmitted has been carefully traced down the spinal cord to the first thoracic sympathetic ganglion ; if this path be interrupted at any point symptoms follow similar to those caused by the local injury to the medulla oblongata. The circumstance that interruption of this nervous pathway at any point causes the appearance of sugar in the urine at once leads to the suspicion that the escape of sugar is not directly caused by the shock of the operation or injury. We are rather brought to the conclusion that the natural absence of sugar from the urine is due to a restraining influence of the nervous system acting continually in a manner to be discussed hereafter, and that the division of the path by which the continual restraint is exercised merely intercepts the inhibitory influence. This is confirmed by the observation that the medulla is in communication with certain afferent nerves, through which also the restraint may be removed. These nerves are the vagi ; division of them leads to a transient appearance of sugar in small amount in the urine ; but stimulation of their cerebral ends brings about the escape of sugar to a remarkable degree. This clearly can only be due to an inhibition by afferent nerves very similar to the inhibition of the heart which follows stimulation of the cerebral end of the abdominal sympathetic nerve in the frog.

The intercepting of this hypothetical restraint by the anatomical section of nerves is not the only way of artificially bringing about diabetes. Sugar may appear in the urine during the action of curare and after a suitable dos of morphia, and also after the injection of dilute saline solutions into the blood-vessels. The probable relationship of these various methods of causing diabetes will be referred to later.

There can be no question that diabetes is a disease affecting the glycogenic function of the liver. In many cases of natural or pathological diabetes, if' all carbohydrates be withheld from the patient, the urine becomes free or almost free from sugar ; and in like manner, if an animal be starved until there is every reason to suppose that its liver has become free from glycogen, and afterwards it be subjected to the operation for producing artificial diabetes, no sugar appears in the urine. Similarly, if an animal be drugged with arsenic, which leads to a rapid loss of all the glycogen of the liver, and afterwards poisoned with curare, the latter drug no longer brings about diabetes. In short, if the liver contains no glycogen no sugar can appear in the urine. This being so, in what special way is the glycogenic function modified in diabetes ? If we assume that the function of the liver is to seize upon all sugar passing along the portal veins from the intestinal canal and store it up as glycogen, in order that it may be piecemeal returned to the blood to be arnt off in distant organs, we can easily review the various conceivable ways in which diabetes might be caused. It must, in the first place, be premised that the blood is unable to contain more than a certain percentage of sugar. When this percentage is overtopped the excess of sugar escapes in the urine. Of