NUTRITION 681 hepatic metabolism ends in the production of glycogeu, which merely waits to be cast out into the blood-current at the call of the body generally. Against this hypothesis, as a complete ex planation 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 circum stance above referred to, that glycogen so readily becomes converted into sugar post mortem, at once leads us to inquire whether a similar conversion is not normally effected during life. The inquiry be comes 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 conver sion, 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 con tain 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 destruc tion 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 differ ence 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, how ever, 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 assump tions to account for the fate of glycogen in the body ; 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 animals, 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 con siderable 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 con version 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 elabora tion of bile. There is strong reason to think that the bile-pigments are derived from the colouring matter of blood, not only from the circumstance of the large destruc tion of blood -corpuscles which takes place in the liver but also from the resemblance or identity of bilirubin and haematoidin, a body derived from extra vasated blood. A large number of facts point very clearly to the conclu sions (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 con clusions, whilst the second rests upon many considerations. The bile-acids unquestionably do not exist in the blood, but are the results of proteid metabolism within the liver-cells. There are strong grounds for believing that urea, CH 4 N 2 Op as well as uric acid, has its principal origin in the liver, which is equivalent to localizing the chief 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 vaso- motor 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 trans mitted 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 injurv 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 communica tion 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 dose 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 after wards 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 burnt 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 per centage is overtopped the excess of sugar escapes in the urine. 01 XVII. 86
