The frequent association of gout and diabetes has long been observed, and in "gouty glycosuria" (Brunton) comparison is made between the chronic hyperemia of the diabetic liver and the acute hyperemia of the gouty joints.

Occasionally persons past fifty years of age who are gouty may present the symptom of glycosuria without other accompanying manifestations of diabetes, such as emaciation and debility. This symptom may persist for a number of years and end in recovery, or the patient may die of some intercurrent disease in no way connected with diabetes.

In a long series of cases of diabetes reported by Ord, gout occurred in over one third, and in some there was arthritis deformans. In these cases not only does the urine contain sugar in excess, but the urea and uric acid are largely increased. It is interesting to remark in this connection that similar dietetic treatment benefits gouty, obese, and diabetic patients, for they live best upon a nitrogenous diet with alkalies. The occurrence of an excess of uric acid in the urine (uricaemia) is often a forerunner of diabetes (Coignard, Comillon). Diabetes is also often associated with neuralgia, phthisis, hepatic engorgement, and congestion. There is no one form of disease of the liver in which diabetes is uniformly or frequently associated. In about one third of the cases a history is obtainable of mental strain or overwork, and in about one third there is a history of alcoholism.

Physiological Experiments

In order to understand fully the dietetic treatment of diabetes, it will be necessary to discuss somewhat at length certain physiological experiments and theoretical causes in relation to aetiology. These topics will be found to throw some light upon the relations of diet to the symptoms. The experiments of Claude Bernard above alluded to were made to determine where the sugar which has been ingested by an animal is destroyed. He was the first to accurately determine the amount of sugar normally present in the blood. According to his estimate, when this quantity does not exceed three parts in one thousand, the limits of health are not surpassed, and sugar does not appear in the urine, as it promptly does when the proportion is increased.

He fed animals heavily upon sugar, killed them, and examined the blood from various blood vessels. In this manner he ascertained that a good deal of sugar is destroyed by the passage of the blood through the lungs, but he also found it to be carried by the hepatic vein, while the portal vein contained a trace only. He demonstrated that the liver, excised from the body and washed free of all blood by a stream of water injected through the portal vein, would, after standing for a few minutes, still yield sugar. He thus proved that the liver is capable of forming sugar by some process which is continued independently of its blood supply. He next searched for the source of the sugar formed by the liver, and discovered the substance, to which he gave the name of "glycogen." Glycogen, or animal starch, is a normal ingredient of the liver cells, in which it is stored in the form of amorphous granules around their nuclei. When treated by diastatic ferments or boiled with dilute mineral acids, it is converted into a grape sugar or glucose. Hensen, of Kiel, discovered glycogen independently of Bernard and at nearly the same time.

This substance, which is isomeric with starch, occurs in the skeletal muscles as well.

Bernard also found that the quantity of sugar which he could collect from the hepatic vein at any time did not increase when the animal was fed upon a large amount of sugar; this circumstance led him to argue that the liver arrests the sugar ingested on its way to the general circulation, and thus acts as a regulator of the amount of sugar contained in the blood.

Man takes his food at comparatively infrequent intervals, and it is important that the energy derived from the ingestion of a large meal of carbohydrates should not be immediately expended, but should be stored in some form which will enable it to be gradually used in the intervals between digestion of meals, and in any emergency when food is withheld for a longer time than usual. The liver affords this means of storing a considerable amount of energy by converting the sugar - brought to it in the portal system which has been absorbed from the intestinal wall - into glycogen, a temporary product which is stored and held back in the liver cells, but which can be readily paid out in small quantities from time to time into the hepatic blood as it leaves the liver. In this manner an excess of sugar ingested or an excess of sugar derived from the digestion of starchy food is normally kept from immediately entering the circulation, and its use is economised by holding it back until it is required for force production.

The ultimate destination of the sugar reformed from the glycogen of the liver is that it is consumed either in the capillaries or intercellular spaces or in the muscular and other tissues of the body by obscure ultimate processes of nutrition, which result in its splitting up into carbonic acid and water with the evolution of heat. In support of this view Claude Bernard proved that there was less sugar in systemic venous blood than in arterial blood.

Bernard extracted with glycerin a diastatic ferment from the liver and blood, which he supposed had the function of converting the glycogen into glucose; this action he called the "glycogenic" function of the liver. The sugar absorbed from the intestines and arrested in the liver he supposed to be there converted into glycogen by the glycogenic ferment. Glycogen is also formed from peptones. Foster says that glycogen may be accumulated in the liver upon a mixed diet, and that it may be in part formed by dehydration of sugar derived from metabolism of proteid food. It is a fact that when diabetes is once established, the elimination of sugar in the urine will sometimes continue in both man and animals kept upon an exclusive nitrogenous diet.

The foregoing experiments, verified by many physiologists, have given rise to three principal theories regarding the origin of glycosuria, which are as follows:

1. It is due to impaired glycogenic function, and the sugar taken as a food is at once passed into the general circulation unaltered.

2. It is due to increased glycogenic function; there is an overproduction of sugar from the glycogen, the latter being derived both from sugar and peptones, and the newly formed sugar is swept into the blood.

3. The conditions of absorption of carbohydrates and of the functional activity of the liver may remain normal, and yet the final combustion of sugar by the tissues or its assimilation by them may be imperfect and lead to its accumulation in the blood and subsequent appearance in the urine.

The three conditions mentioned above imply either diminished activity of the liver, increased activity of the liver, or a normal liver, the fault being in other tissues of the body.

Either one will give rise to the presence of an abnormal amount of sugar in the blood (glycohaemia), which is excreted by the kidneys (glycosuria). To aid in substantiating these theories, it should be proved: (a) That there is a definite relation between the quantity of sugar that leaves the liver and the quantity of glycogen remaining in the liver, (b) That the "glycogenic ferment" resembles diastase, (c) That the glucose passing through the hepatic vein is identical with the sugar which can be formed from starch by fermentation, (d) That there is a definite relation between the quantity of hydrocarbons (and peptones) entering the liver and the quantities of glycogen and glucose subsequently obtained. The experiments of Bernard have been in the main confirmed by other physiologists, but there is exception taken to some of them, and his theories are not universally accepted.

It is probable that in the majority of cases the primary difficulty is to be found in altered metabolism in the liver.

Pavy strongly favoured the view that diabetes is due to a faulty action of the liver in not preventing the sugar which is brought to it by the portal vein from reaching the general circulation.

The essential difference between the theories of Bernard and Pavy in regard to the glycogenic function of the liver concerns merely the final destination of the glycogen. Both agree as to the primary conversion of sugar from the portal vein into glycogen, but while Bernard believed that the glycogen is reformed into glucose and consumed in the tissues, Pavy held that the normal use of glycogen is in the formation of fat.

Pavy believed that a small amount of sugar may be absorbed by the lacteals during the digestion of sugars or starches passing through the thoracic duct directly into the venous circulation without entering the liver. This he considered a normal condition. It, however, requires the use of far more delicate tests than those commonly employed in clinical work to detect the minute traces of sugar in the urine which Pavy claimed are normally present.

Pavy has propounded another ingenious theory to account in part for diabetes, even though other theories be not wholly abandoned, It is that the intestinal epithelium of the villi ordinarily exerts a sort of glandular control over the sugar absorbed from the bowel, and converts it into glycogen and fat as it reaches the blood. Failure to perform this function results in the production of glycosuria. This failure, Pavy holds, is due primarily to faulty nerve action affecting the calibre of the arterioles and capillaries with hy-peroxidation, which favours the too rapid conversion of carbohydrates into glucose, causing glycosuria. This theory has been somewhat severely criticised by Paten, and is opposed to Seegen's views, but it does not exclude belief in the storage of carbohydrates as glycogen in the liver - it is merely accessory to it.

If the liver of an animal be rapidly excised and cut into small fragments to prevent further fermentation, it will be found on analysis to contain sugar in a small proportion which varies, according to different observers, between 0.2 and 0.6 of 1 per cent (Bernard and Seegen); hence but little sugar is to be found in the liver during life, or immediately after death, and it has been suggested by Flint that whatever sugar may be found is immediately washed out by the hepatic blood stream. If the excised liver be not boiled, but be allowed to remain at the body temperature for some minutes, or if the portal circulation be suddenly cut off while the liver remains in the body, it is found that the formation of sugar continues for at least an hour, owing to a process of fermentation which produces it from glycogen. From these and other experiments it is believed that the glycogen stored in the liver is constantly but gradually converted into sugar, which is carried off in the general circulation in such small quantities that it is often difficult to detect its presence in the blood.

Glycogen is found in the muscles, and in some other tissues of the body, and it has been suggested that sugar might be formed in the blood vessels, quite independently of the liver, by a ferment carried in the blood, but the hepatogenous origin of the glucose is the view generally accepted at present.