THE PROTEINS IN THE CAUSATION OF DIABETES.

Whatever the dietetic errors that provoke the diabetic condition it now seems certain that it is not the carbohydrate alone that is at fault. Primarily diabetes occurs only in an individual whose metabolic organization is very weak, but it will not occur unless provoked by some gross and persistent dietetic abuse. Perhaps overeating is the most potent factor in its causation. On the other hand, in races that consume large quantities of farinaceous food with only a minimum of proteins or fats, diabetes is very rare. Neither underfeeding nor poverty is a cause; it is rather a disease of the rich. When the expensive proteins are consumed in large quantities by those who can afford them and by those who lead a sedentary life, diabetes is likely to follow. It is more than likely that even without a proper balancing of the food a reduction in the total quantity of food consumed would in itself reduce the incidence of diabetes. It is the protein element that must be curbed rather than the carbohydrates in diabetes. In the newer understanding of this disease this is realized, and far from withdrawing the carbohydrates they are often advocated as a cure for diabetes. It is from this that the so-called oatmeal cure received its reputation. Heretofore the dietetic treatment of diabetes contemplated an almost unlimited supply of proteins and a complete withdrawal of the carbohydrates. Yet it was understood that the threatening of an acid condition was a sign for the restoration of the carbohydrates, in spite of the increase of the sugar output.

Overindulgence is perhaps the most important factor in the production of a systemic hypoalkalinity. The taking of food in which the proteins predominate increases the acid production and increases the hypoalkalinity. The proteins, in fact, are acid foods. It is pernicious in any glycosuria to allow an excessive meat diet. Very often a marked limitation or even abstinence for a period will of itself cause the disappearance of the sugar. Moreover, the defective utilization of the sugar is not nearly as ominous to the organism as an increase in the acid state of the body as a result of protein intoxication or excess. Indeed, it is because of the defective utilization, where only a small amount of sugars can be oxidized at one time out of the amount supplied, that the sugars must be pressed so that at least this small amount can always be carved out of the total supply. There is no harm in the presence of sugar in the urine. It is merely an index of the condition. The amount of sugar only shows how much of it the system could not utilize.

Before much improvement in the carbohydrate

utilization can occur the nitrogenous equilibrium must be established. The prescribing of a meat diet in this weakened metabolic organization but increases the nitrogenous inequilibrium. Those individuals who exist on the diet heretofore prescribed for the diabetic-that is, high protein and low carbohydrate-are the ones most likely to be attacked with diabetes. Diabetics get along much better on a normal well balanced diet than on any special diabetic dietary that has not the balancing as its chief purpose. Because the basic cause of diabetes is a weak metabolic organization the diet must be at a minimum in order to tax the metabolic process least, but the diet must favor the carbohydrates rather than the proteins. The diet is the provoking element in a damaged organization. With normal metabolism no one can foretell how much abuse the organism can stand without injury. If organotherapy has any value in the treatment of diabetes it is because the basic metabolic weakness in diabetes is probably of glandular origin. It is most probable that not only the pancreas but also the other glands of internal secretion are concerned, and the gland extracts usually administered supply a deficiency that the defective glands cannot.-New York Medical Journal, July 27, 1918.

JOBS ARE CLASSIFIED.

In an article on "Modern Industrial Medicine," in the August number of the American Medical Journal, C. G. Farnum says:

"In a really modern industrial plant, where the department of medical supervision is worthy of the name and where the safety engineer and the superintendent of employment are alive to modern needs, the individual jobs are classified and indexed as to availability for physical defectives. How simple the whole procedure then becomes! What matters it how many arms, or legs, or eyes, or ankylosed joints a man chances to possess?

"Some of us have statistics concerning a period of years that bring out two striking facts in connection with this work: That the labor turnover varies inversely as the physical defects of the laborer, and, that the worse the physical defect, the less the accident incidence. These statistics may be considered the measure of the physical and mental compatibility of the man with his job."

Vol. XVIII

Original Articles

THE HYPOPHYSIS AND HYPOPHYSEAL DISEASE.

E. W. SCHNOOR, M.D.

GRAND RAPIDS, MICH.

Confined to a small recess in the sphenoid bone is a ductless gland which was first described by Vesalius in 1553 as "the glans pituitans incipiens," believing it secreted mucus. In 1778 it was termed the hypophysis cerebri by Sommering.

It

The pituitary body or hypophysis cerebri is a small somewhat rounded organ occurring in all vertebrates except the lowest fishes. weighs from 5 to 10 grains. According to Zander its size is quite variable: 6 to 10.5 mm. in the sagittal diameter, 10 to 14.5 mm. in the vertical, 5 to 9.75 mm. in the transverse. The dura mater which forms the inner walls of the cavernous sinus is its main support.

This gland consists of three parts: a large glandular anterior lobe or pars anterior, a smaller pale posterior lobe or pars nervosa and the pars intermedia of Herring.

The pars anterior develops from an upgrowth of the buccopharyngeal ectoderm about the fourth week. This diverticulum is known as Rathkes pouch and its lumen becomes nipped off by the sphenoid bone later. Histologically this lobe consists of a vascular mass of epithelial cells which Flesch describes as two types: chromophobe or neutrophilic non-granular protoplasmic cells and chromophile or granular protoplasmic cells. The latter type Schoenemann classifies as to staining characteristics of the granules, eosinophile cells and basophile or cyanophile cells. Sections from different parts of the gland differ as to the predominating type of cell, central area the eosinophiles seem to be more abundant while at the periphery the basophiles. Erdheim found the chromophobe cells predominating in infancy. Later the chromophile cells predominate. A

No. 3

functionating gland as described by Delille contains an abundance of colloid substance both intra- and extra-cellular, while in gland nearly exhausted the cells are granular, stain poorly, nuclei are pale and some neutrophilic cells without vacuoles. The colloid substance has been shown by Thaon and more recently by Grünbaum and Grünbaum to discharge into the blood stream. This glandular lobe is surrounded by a connective tissue capsule.

Sometimes a band of epithelial cells is found traversing the sphenoid bone connecting the pars anterior with a small mass under the pharyngeal mucosa, the Rachendach Hypophyse of Erdheim and Haberfeld. This mass of cells may develop into functionating tissue, both normally apparently and as a compensatory hypertrophy in pathological conditions of the hypophysis. Accessory glandules have been found.

The posterior lobe or pars nervosa, praetically non-vascular, develops from a downgrowth of the primitive third ventricle with which it communicates by a stalk or infundibulum. It is composed of loose neuroglial and ependymal tissue, invested by an epithelial layer, the pars intermedia.

The pars intermedia is derived from the posterior layer of Rathkes pouch which becomes thickened. The pars intermedia may secrét a colloid substance which passes into the pars nervosa. This colloid substance is probably the same substance which Herring describes as hyaline bodies occurring between the nerve fibers. From these spaces Herring believes the substance is probably absorbed by the lymphatics and carried into the infundibular cavity and thence to the third ventricle. Cushing and Goetsch claim that the cerebro-spinal fluid contains the active principle of the posterior lobe. Brown pigment granules are found in this part of the gland which Vogel in his researches has shown vary as to age, sex and disease. Under ten months they are usually absent but gradually increase after four years being more abundant in males. Stumpf con

controls were negative as regards weight and also the skeleton as shown by X-ray. In Cushing's experimental work life could be prolonged in threatened hypophyseprivia by the injection of whole gland or interior lobe extract whereas posterior lobe extract would fail.

Prolonged administration of either whole gland extract or of pars nervosa alone leads to marked nutritional disturbances and alterations in various organs of the body. The suprarenals are at first stimulated and later exhausted. The thyroid shows decreased colloid and there is a tendency to hypothyroidism, probably due to vaso-constriction in the gland. Liver and spleen show necroses. Kidneys are congested and there is an increase in the volume of the glomeruli. Lungs are congested. Attempts at implantation or transplantation have been unsuccessful. Exner's rats showed an increased growth for a short time. Crowe, Cushing and Homans prolonged the life of animals after total hypophysectomy by immediate reimplantation of the gland into the cerebral cortex which remained viable for at least a month.

Disturbances in the internal glandular system affect the pituitary body. Erdheim and Stumme examined 122 hypophyses of pregnant women and concluded that the organ increases in size and weight in pregnancy and after several pregnancies becomes permanently enlarged, there being a tendency to adenomatous hyperplasia in fully 10 per cent. The hyperplasia is chiefly of the chromophobe cells. Vogel has observed a decrease in the brown pigment granules in the posterior lobe in pregnancy. Gley's thyrodectomized rabbits showed a hypertrophy of the gland. Fischero noticed that castrated steers and cocks all had at autopsy several months later, a hypertrophy of the anterior lobe. Comte noted marked hypertrophy in 12 of 13 cases of goitre with degeneration of the thyroid exclusive of Basedows, while Benda found the hypophysis small in Basedows.

What role this small body plays in the development and maintenance of physiological equilibrium has been the subject of much controversy. Among the early experimenters are Marinesco and Vassale and Sacchi. All their animals died following total hypophysectomy. Friedman and Mass in 1900 reported that extirpation of the pituitary body was compatible with life. La Monaco and Rynbeck in 1901, Gagleo in 1902 and Pirrone in 1903 also arrived at the same conclusion. Fischero in 1905 found that partial removal

of the gland in young chickens checked their growth. Paulesco in 1908 extirpated the gland in 22 dogs and 12 cats. Most of these animal's developed a peculiar symptom complex known as cachexia hypophysepriva resulting in death in two or three days. Few survived but at autopsy showed viable anterior lobe cells. He thus concluded that total removal of hypophysis was fatal while partial removal of anterior lobe was compatible with life. Reford and Cushing in 1909 reported results that agreed with Paulescos observations. In 1910 Crowe, Cushing and Homans conducted a more detailed study of a larger series of canine hypophysectomies and again confirmed Paulesco's contention, but the average duration of life. was longer than Paulesco's observations showed. Puppies lived longer than adult dogs. They further showed that total removal of the anterior lobe was equivalent to total removal of the gland and that animals deprived of the posterior lobe survived indefinitely. Partial removal of the anterior lobe in some of Paulesco's and Cushing's animals lead to an increase in the deposition of fat, sometimes associated with polyuria and trancient glycosuria with shedding of hair and lessening of sexual activities.

Cachexia hypophyseprivia or the symptomcomplex produced by the removal of the anterior lobe or the whole gland usually appeared from 30 hours to two weeks after the operation depending on the age of the animal. Early usually a transient glycosuria and polyuria. The animal becomes apathetic, inactive, stiff, gait is unsteady, temperature becomes subnormal, pulse and respiration slow, back arched, incurvature of tail, irregular contractions and coarse movements and finally coma and death.

Handelsmann and Horsley in 1911 issued a preliminary report refuting Cushing and coworkers' conclusions, total removal of the hypophysis in monkey was not incompatible with life and further more that three animals, a dog, cat and monkey survived total removal of the anterior lobe. Paulesco also observed that mere separation of the infundibulum lead to death similar to total hypophysectomy. Cushing disagrees showing it corresponds to partial removal of anterior lobe by incomplete destruction of blood supply to anterior lobe. Handelsmann and Horsley also disagreed and more recently Morawski who experimented with monkeys and suggested that Paulesco's result was probably due to opening the third ventricle. Total extirpation of hypophysis by Ascoli

and Legnani was followed by cessation of development and a tendency to obesity. The epiphyseal ossification was delayed, teething occurred late and sexual organs remained infantile. The thyroid showed colloid atrophy, thymus premature involution being one-fifth normal volume, spleen atrophic and cirrhotic, malpighian follicles has disappeared, the fasicular and reticular zones of the suprarenals reduced to one mixed layer. The longest survival was eight months. Aschner recently declared that the pituitary body was essential so far as development is concerned. He noted no genital changes following removal of the posterior lobe. Sweet and Allen very recently announced that the entire canine hypophysis can be removed without danger to life.

Very interesting carbohydrate tolerance experiments were reported by Goetsch, Cushing and Jacobson in 1911. Simple operative manirulation of the infundulum produced a transient hyperglycaemia and for a few days an alimentary glycosuria. This they attributed to setting free of a reserve deposit of posterior lobe secretion which acted upon the liver causing a sudden release of glycogen. If a considerable portion of the posterior lobe with its epithelial investment was removed or the secretory discharge through the infundibulum interfered with by damaging it or by scar tissue later, the temporary lowering of tolerance was followed by an abnormal increased tolerance for sugars. This would be lowered by the injection of posterior lobe extract. Removal of the anterior lobe partly resulted similarly to the manipulation of the infundibulum, but no over tolerance followed, while injection of posterior lobe extract as before reduced the tolerance, anterior lobe extract being inactive or far less potent in this respect. Thyroid extract was also tried with negative results.

Metabolism in nearly hypophysectomized dogs was observed by Benedict and Homans: the development of the animals ceased, their sexual activity did not develop and if already established was profoundly affected, excessive fat deposits occurred and accounted for the increased weight, body temperature remained slightly subnormal while pulse and respirations became slow. Total metabolism as measured by C02 output was markedly decreased. Aschner and Porges have demonstrated a decreased consumption of oxygen after loss of the pituitary body.

Further studies in carbohydrate metabolism were reported by Weed, Cushing and Jacobson

in February 1913. They summarize their work as follows: (1), Piqure of hypophysis in the rabbit is comparable in its glycosuria response to a piqure of Bernards so-called sugar center in the fourth ventricle. (2), Stimulation of the superior cervical ganglion by faradization or by manipulations necessary for exposure caused glysuria in dog, cat and rabbit. (3), Stimulation of superior cervical ganglion after exclusion of all possible downward impulses to abdominal viscera by way of vagi, cervical sympathetic trunks or spinal cord leads to glysuria. (4), Stimulation of superior cervical after separation of all synapses of the sympathetic system by administration of nicotine causes glysuria. (5), Direct faradic stimulation of the hypophysis itself after exposure by a transphenoidal operation gives glycosuria even after preliminary transection of the spinal cord and cervical sympathetic trunks. (6), If the posterior lobe of hypophysis was previously removed by operation the usual stimulation of superior cervical ganglion failed to give glycosuria. (7), Direct faradic stimulation of hypophysis provoked glycosuria even after transection of spinal cord above the splanchnics. (8), A Bernards piqure will likewise cause glycosuria even after transection of spinal cord above the splanchnics. These results were obtained only when there was mobile glycogen in the tissues.

Our knowledge concerning the pathology of this small organ is practically limited to neoplasms. Munzer classifies the pathological processes as follows: 1, atrophic conditions; 2, hypertrophic and hyperplastic conditions; 3, tumors. Scattered through the literature I find reports of the following types of tumors: granulomata, colloid and cystic enlargements, chromophobe-eosinophile and basophile adenomata, carcinoma, sarcoma, angio-sarcoma, periepithelioma, endothelioma, teratoma (Hecht), glioma and psammoma.

Circulatory changes, anemia, hyperemia and hemorrhages are stated to occur. Lewis finds that the most common tumors of the infundibulum develop from inclusions of the craniopharyngeal duct and may be cystic or solid. These are more frequently, associated with Frohlich's syndrome than any other type of intra-cranial tumor. Struma and adenoma of the anterior lobe are the most frequent and practically constant findings in acromegaly. Fischer has emphasized this fact most forcibly recently. Erdheim considers an eosinophile adenoma characteristic of acromegaly. Pars