Pavy's Theory

The other view owes its origin to Pavy, who assents to the doctrine that glycogen is derived from the excess of sugar in the portal vein, but that once formed it is never again in normal circumstances reconverted into sugar, in which form he maintains that it would be at once excreted by the kidney. On the other hand, he contends that the glycogen or carbohydrate molecule is in the liver tacked on to the protein molecule, and thus conveyed to the tissues safely without fear of excretion by the kidneys. He utilises the sidechain theory,* and considers that the carbohydrate molecule attaches itself to a haptophore group, and so being carried to the tissues, is there dissociated for utilisation.

He declares this is proved by the hyperglycemia in diabetes not being in proportion to the glycosuria. When the sugar is not incorporated with the protein molecules of the living cells, then it appears in the blood, is expelled by the urine, and diabetes takes place. Even if it be locked up properly in association with the protein molecule it may not be oxidised by the tissues, and in the same way diabetes ensues. He maintains that if the liver be frozen immediately after death so as to destroy the glycolytic ferment, analysis will show the percentage of sugar to be higher than in any of the other parts of the body. His theory, indeed, is tantamount to an assertion that the carbohydrate material is converted into fat and protein, which are then metabolised in the usual manner.

Although the classical view retains the field, careful reflection will reveal the fact that we cannot afford heedlessly to dis- card Pavy's view. It has been proved that glycogen can be formed probably from all proteins, but certainly from those which contain a carbohydrate molecule, and it is indeed found in animals which consume no carbohydrate food. It is known also from feeding experiments that next to fat, carbohydrates are the most powerful fat producers, and that in diabetes both fat and protein contribute to the manufacture of sugar. On a diet restricted entirely to protein 2.8 parts of dextrose to one part of nitrogen appear in the urine. The diet also contains much more carbohydrate food than would account for 300 grams of glycogen, and the excess, therefore, can only be utilised in the formation of fat and protein.

* Ehrlich regards living cells as possessed of constitutions analogous to the ring of the benzene molecule, to which as a central nucleus outlying molecules termed sidechains or receptors are attached. These are supposed to subserve the nutrition of the cells by combining with food molecules, oxygen, etc, circulating in the blood. There are several varieties of receptors: (1) Single haptophore (i.e., combining) groups enabling food molecules to become anchored to the cell; (2) those consisting of two groups, one haptophore and the other digestive; (3) those with two haptophore groups, to one of which the food molecule anchors itself, while the other attracts molecules possessed of digestive properties. There are thus specific receptors for the different varieties of protein in the blood, and as an explanation of the method whereby the cells assimilate food and normal tissue nutrition is carried on, this theory is illuminating, feasible, and probably represents the true state of affairs.

Accepting the view that glucose is carried by the blood stream to the muscles for oxidation, there are grounds for believing, although no direct proof has ever been offered, that the preliminary stage in this process is a reconversion into glycogen. In any case no glycolytic ferment has been discovered in the blood, and it is not at all probable that any exists there, as hardly any change takes place in its content of glucose even some hours after it has been drawn. Even the muscles in which the actual combustion takes place are apparently devoid of any such enzyme, as expressed muscle juice has no glycolytic effect. As excision of the pancreas is always attended by cessation of the destruction of dextrose, one would hope to be successful in discovering such a ferment in that organ, but neither pancreatic extract nor expressed pancreatic juice can produce glycolytic changes. Cohnheim, however, has demonstrated that a mixture of muscle juice and expressed pancreatic juice possesses marked glycolytic power; and hence it is assumed that the enzyme in the muscle is ineffective until it has been activated by something in the nature of an internal secretion from the pancreas.

In the presence of oxygen the final stage in the decomposition of carbohydrate food takes place, carbon dioxide and water being formed. When glycolysis occurs anaerobically, there is first a formation of alcohol and subsequently of lactic and β oxybutyric acids, each of these substances being produced by its appropriate ferment.

From what has been said we may infer that glycosuria may be occasioned either by over-production of dextrose in the liver or a want of destruction of dextrose in the tissues.

The former hypothesis is unlikely, as we should expect to find that when all the glycogen of the liver had been decomposed, sugar would cease to be formed, and after death none would be discovered. But we know that in diabetes sugar persists in the urine until the moment of death, and can be found in the liver after death. The existence of alimentary glycosuria must not, however, be forgotten. Some forms of this condition may be due to the loss of the glycogenic function of the liver, but it is quite possible to occur in health from an overfilling of the glycogenic reservoir, due to the saturation of the system with soluble carbohydrates. The assimilation limit of milk sugar is only 50 grams, so that lactosuria is easily produced, but cane sugar and laevulose may be found in the urine after excessive ingestion of these substances.

The latter hypothesis is generally accepted as the etiological factor in the production of diabetes, the body cells being capable of making but an imperfect use of the sugar. This applies particularly to the muscle cells, probably because, as has been already hinted, they have lost the power of first converting into glycogen the glucose presented to them by the blood stream. In any case the respiratory quotient, i.e., the relation of carbon dioxide excreted to oxygen inhaled, which amounts in carbohydrates to 1 as nearly as possible, is in diabetes only about .7, the factor for protein and fat, and that even when dextrose is supplied in the food.

An interesting new conception of the metabolism of carbohydrates which incidentally lends some support to Pavy's theory is that enunciated by Benjamin Moore. He points out that no sugar is present in blood corpuscles, but asserts that it exists in the serum in some form of feeble union with the proteins. If a stream of carbonic oxide be passed through a sample of blood, and this be then subjected to dialysis, the amount of sugar passing into the dialysate is considerably increased above the amount in the case of blood not so treated. As a stream of air to remove the carbonic oxide restores the sugar yield in the dialysate to the normal amount, it is clear that the sugar must exist in a condition of adsorption with the protein.

In hyperglycemia, therefore, there is an excess of sugar above that which is capable of entering into union with the protein, and it is this excess which is seized upon and thrown out into the urine by the kidney cells. Sugar appears in the urine of a living animal compelled to breathe air containing more than a certain percentage of carbon dioxide, even although it may contain a greater proportion of oxygen than the normal. As much as 11 per cent, of sugar is found in the urine of dogs subjected to prolonged ether anaesthesia. In the liver cells there is union between the bioplasm and the sugar before glycogen is formed. Glycogen, up to a certain maximum limit at which it separates as granules, can also exist in union in the cells, because it can by appropriate measures be separated from hepatic tissue long before granules appear. It has been found that glycogen injected subcutane-ously does not appear in the urine, whereas dextrin does, which might indicate that glycogen was absorbed as such by the muscles, whereas the dextrin could not be utilised, as the blood contains no dextrinase. However that may be, in any case in the normal subject carbohydrates are katabolised into carbon dioxide and water, which are excreted by the lungs, the kidneys, and the skin.

In all probability the first stage in this process is the replacement of two hydrogen atoms of dextrose (C6H42O6) by one of oxygen, thus forming glycuronic acid (C6H40O7), a substance usually found in diabetic urine. This oxidation is a simple matter, very different to the later stages, which involve a splitting up of the linked carbon atoms, and probably this is the role of the internal secretions of the pancreas.