Raw Pancreas Research Articles

Good, Bad or Offal? The Evaluation of Raw Pancreas Therapy and the Rhetoric of Control in the Therapeutic Trial, 1925

In 1925 a debate erupted in the correspondence columns of the British Medical Journal concerning the effectiveness of eating raw pancreas as a treatment for diabetes. Enthusiasts were predominantly general practitioners (GPs), who claimed success for the therapy on the basis of their clinical impressions. Their detractors were laboratory‐oriented ‘biochemist‐physicians,’ who considered that their own experiments demonstrated that raw pancreas therapy was ineffective. The biochemist‐physicians consistently dismissed the GPs' observations as inadequately ‘controlled’. They did not define the meaning of ‘control’ in this context, although it clearly did not have the term's present‐day meaning of a trial employing an untreated comparison group of patients. Rather, the physician‐biochemists' ‘properly controlled’ experiments involved careful regulation of their patients' diet and other environmental factors, and evaluation of the therapy's success through biochemical, rather than just clinical, criteria. However, my analysis suggests that these factors alone are inadequate to account for the biochemist‐physicians' dismissal of the GPs' work as ‘uncontrolled’. I suggest that the biochemist‐physicians were deliberately exploiting the powerful rhetorical connotations of the term ‘control’. Ultimately, they implied that only a trial which they themselves had conducted could be deemed ‘adequately controlled’.

Treatment of pancreatic degenerative atrophy with raw pancreas homogenate and various enzyme preparations.

SummaryTwo dogs suffering from pancreatic degenerative atrophy (PDA) had the cranial part of their jejunum cannulated. The food was supplemented with commercial enzyme preparations as follows: powder, granules, capsules, enteric coated tablets and finely chopped raw pig pancreas. Jejunal samples were withdrawn through the cannula at 1/2 hour intervals for 6 hours after feeding. The activities of proteases, amylase and lipase were determined in jejunal samples, in faeces and in the food. The control material comprised 14 control dogs and one “subclinical” PDA dog.The highest lipase activities in the jejunal samples were achieved using raw pig pancreas. Commercial enzyme preparations yielded activities that were only one tenth of those attained with raw pancreas. With raw pancreas the jejunal lipase activities were not as high as in the control dogs but exceeded those in the “subclinical” PDA dog. Raw pancreas and commercial enzyme preparations increased the proteases and amylase well beyond the activities found in the jejunum of the “subclinical” PDA dog.ZusammenfassungBehandlung der degenerativen Pankreasatrophie mit rohem Pankreashomogenat und verschiedenen Enzympräparaten: Bei zwei Hunden mit degenerativer Pankreasatrophie wurde der craniale Abschnitt des Jejunums mit einer Kanüle versehen. Das Futter wure mit folgenden Formen von Enzympräparaten supplementiert: Pulver, Granula, Kapseln, umhüllte Tabletten und stark zerkleinertes rohes Schweinepankreas. In halbstündigen Abständen wurden bis 6 Stunden nach der Fütterung Jejunumproben via Kanüle gewonnen. Die Aktivität der Proteasen, der Amylase und Lipase wurden in den Jejunumproben, den Faeces und im Futter bestimmt. Als Kontrollen dienten 14 Kontrollhunde und ein Hund mit “subklinischer” degenerativer Pankreasatrophie.Die höchste Lipaseaktivität wurde in den Jejunumproben nach Verabreichung von rohem Pankreas erreicht. Mit kommerziellen Enzympräparaten war die erreichte Lipaseaktivität 10mal niedriger. Nach Verabreichung von rohem Pankreas war die jejunale Lipaseaktivität nicht so hoch wie bei den Kontrollhunden, aber höher als bei dem Hund mit “subklinischer” degenerativer Pankreasatrophie. Sowohl rohes Pankreas als auch die kommerziellen Enzympräparate erhöhten die Aktivität der Proteasen und der Amylase im Jejunum deutlich gegenüber denjenigen des Hundes mit “subklinischer” degenerativer Pankreasatrophie.

The effect of chlor-iso-propamide on experimentally induced resistance to insulin

A study was made of the effect produced by sulfanilamides on the insulin resistance, experimentally induced in depancreatized dogs. Experimental animals with extirpated pancreases received 150 grams of raw pancreas with food (daily), a certain dose of insulin, and contrainsular hormones with an always definite food regimen. As established, thyroidin, ACTH, adresone, and prednisone given in definite doses considerably increased the insulin requirement, whereas chlor-iso-propamide considerably decreased this requirement. Investigations demonstrated that, instead of increasing the insulin dose, one may intensify its effect by chlor-iso-propamide administration.

GROWTH AND REPRODUCTION OF DEPANCREATIZED CHICKENS.

Depancreatized chickens quickly cease to lay eggs; but they will resume laying when 20% raw beef pancreas is included in the feed. When egg production ceases in depancreatized chickens it is accompanied by atrophy of the ovary and oviduct. This process is reversed by the inclusion of raw pancreas in the feed. While the ovary and oviduct atrophy, the adrenal and thyroid appear normal, paralleling the results obtained when the pituitary stalk is sectioned. The cessation of egg production is probably caused by an impairment in the release of gonadotrophic hormones as a result of undernutrition. Replacement therapy with gonadotrophic hormones [pregnant mare's serum (PMS)] stimulated the growth of the ovary and oviduct but did not restore egg production. This failure may have been due to the use of mammalian hormones, or to failure to use LH or HCG (which may be required) as well. Following pancreatectomy, comb growth in male chickens was initially retarded; however, 7 months after the operation, the area of the comb of depancreatized chickens was essentially equivalent to that of intact birds. Male chickens failed to produce semen after pancreatectomy; the production of semen and of viable sperm resumed when these animals were fed raw pancreas. (Endocrinology74: 207, 1964)

Etiology of experimental diabetes produced by dietary factors.

Experiments described in this report show that diabetes can be produced by protein-fat diets in dogs after subtotal pancreatectomy or ligation of the main pancreatic duct. In its early, mild stage, this type of experimental diabetes is reversible, i.e., upon the administration of lipotropins, in the form of raw pancreas, the carbohydrate metabolism reverts to normal, and becomes abnormal again when the lipotropins are withdrawn. This phenomenon is analogous to the development of transitory diabetes in normal subjects under the influence of protein-fat or high fat-low protein diets. According to unequivocal proof, furnished by several investigators, most convincingly by Himsworth, the immediate cause of the deterioration of carbohydrate metabolism under this condition is insulin resistance (inhibition of insulin action), but the factor that generates insulin resistance remained obscure. Porges and Adlersberg suspected fatty infiltration of the liver as the generator of insulin resistance, and the present s...

An orally-active, heat-labile factor in pancreas which induces salivary gland hypertrophy in rats.

Rats fed a stock diet supplemented with graded amounts of raw pancreas exhibited retarded growth and a marked hypertrophy of the salivary glands, effects which were proportional to the level of pancreas fed. These effects did not occur when heated pancreas or other raw tissues were fed.

On the Cells of Hypophysis after a Total Pancreatectomy

This study was started by HOUSSAY in 1930, when he was extirpating the anterior lobe of the hypophysis from diabetic dogs after pancreatectomy, which was followed by HOFFMANN in 1931 who found the fact that the extract from the anterior lobe had an action to cause fat liver. In 1937 MACKAY found that by extirpating the adrenals, the action that produces fat liver was suppressed. From this series of studies it was made clear that the anterior lobe of the hypophysis and the adrenals played an important role in fat metabolism of the liver. Furthermore, MACKAY reported that the extract from the anterior lobe have a ketogenic action and this action, too, was suppressed by the extirpation of the adrenals. And it can be understood that the anterior lobe of the hypophysis and the adrenals also have relations with sugar metabolism Apart from the upper stated facts, the author was able to prove histologically from experiments where the pancreas was removed partially or totally that fat and probably sugar metabolism in liver cells have an intimate relationship with the adreno-coritcal function (See previous chapter). From these facts the author had to come to a conclusion that there was a need to study the anterior lobe of the hypophysis from a cyto-morphological standpoint at the time of total pancreatectomy. And from this study the author tried to clear the relationship between fat and sugar metabolism with the hypophysis- adrenocortical system. In preparing the materials, the animals of the first group received 35g/kg of raw pancreas mixed in their diet on the 1st, 3rd, 5th and 7th day after total pancreatectomy, while those in the second group had it mixed in their diet every day after operation. Then, after the 1st, 3rd, 5th, 7th, 10th, 20th days, 1 and 3 months after the operation the hypophysis was removed and histological specimens were made as in the previous chapter. And following results were obtained.1. When total pancreatectomy was performed on dogs there was an early structural change in the anterior lobe of the hypophysis and this change was most prominent on the 5th day after operation. This change appeared despite that raw pancreas was added to the diet, but it gradually recovered from the 7th day on and after the 2 months it was back to its nearly normal state. Therefore, it can be presumed that the anterior lobe of the hypophysis have relations with fat and sugar metabolism in the liver.2. The cytological change at the time of total pancreatectomy was that there was an increase of active cells among the 1st and 2nd type cells. Contrary to this, the 3rd type cells showed a decrease and at times nearly disappeared. These changes were also more obvious in type 2 cells than in type 1 cells.Histological changes seen in the anterior lobe of the hypophysis after total pancreatectomy and the author's findings in the previous chapter, that is, cytological changes in zona fasciculata of the adrenal cortex appeared both at about the same time, which means that the hypophysis and the adrenal cortex have intimate rerations with each other. And it is thought that this will prove that both of them as factors in the hypophysis adrenal cortex system plays a series of important parts for fat and sugar metabolism in the liver cells.4. The appearance of cells with metachromatic granules in the posterior lobe of the hypophysis after total pancreatectomy could be thought that it means there is a further intimate relation between the pancreas and the hypophysis.

Operative Procedure on the Pancreas and its Relation with the Cells of the Adrenal Cortex

Since SELYE reported on his theory of general adaptation syndrom studies on endocrine glands have made great progress. Especially, since the discovery of steroid hormone, it has been proved experimentally that the adrenal cortex plays an important part in the metabolism of fat and sugar. Therefore it can be presumed that the pancreas and the adrenal cortex have deep relations. If that is so, when an operative procedure is performed on the pancreas it can be thought that some kind of changes should occur in the hypophyso-adrenal system. Under this idea, in experiment one partial pancreatectomy and in experiment two total pancreatectomy were performed with giving post-operatively drugs preventing fat liver to see histological changes in the cells of the adrenal cortex. The results were as follows:1. When partial and total pancreatectomy were performed in dogs there was an obvious change in the adrenal cortex, especially in zona fasciculata.2. Structural changes appeared much earlier and in higher degree in the adrenal cortex when the caudal part was resected in comparison to the capital part.3. Four fifth resection of the caudal part of the pancreas showed a higher degree of change in zona fasciculata than a half resection and took much longer time to its recovery to normal.4. From these results it can be presumed that zona fasciculata has some kind relation with LANGERHANS' islands, especially their β cells.5. Total piancreaectomy showed a much higher histological change in zona fasciculata that in its partial resection.6. When drugs preventing fat liver was given after total pancreatectomy histological changes in zona fasciculata remained in a lighter degree and recovered to its normal state after a certain period. Giving raw pancreas showed a greater effect than just giving trypsin and methionin.7. From findings in the liver cells it seems as if zona fasciculata not only has relations with fat metabolism, but also with sugar metabolism.

Phospholipid Utilization in the Diabetic Dog.

Summary and ConclusionsPhospholipid tagged with radioactive phosphorus- was injected intravenously into normal and diabetic dogs. From the rate of disappearance of the tagged phospholipid from the blood stream and the plasma lipid phosphorus level, the rate of utilization of phospholipid was calculated. It was observed in both normal and diabetic groups that the rate of utilization was roughly proportional to the plasma lipid phosphorus concentration. The absolute utilization of plasma phospholipid was slightly lower in the diabetic group, but the proportion of plasma phospholipid utilized per hour was significantly higher in this group. Administration of insulin and sugar to diabetic dogs caused no significant change. Administration of raw pancreas to diabetic dogs increased the absolute utilization very markedly and the proportion utilized per hour only slightly.

CELIAC SYNDROME

The therapeutic problems presented by congenital pancreatic deficiency form two groups, those relating to nutrition and those presented by the characteristic infections of the respiratory tract. It is possible that the susceptibility to infection is a sequel to the difficulty in digestion. The present study was begun in the hope that a dietary regimen might be worked out which would result in adequate nutrition and growth and in improved resistance to pulmonary infection. For nearly a hundred years it has been known that when pancreatic secretion is excluded from the intestine digestion is impaired and that pancreatic ferments are required for normal digestion of three of the main constituents of food, protein, starch and fat. Moreover, it has been found possible to maintain adult pancreatectomized dogs in good health by selection of diet, addition of vitamins and of raw pancreas to the diet and use of insulin. 1 The dietary

LIPID METABOLISM IN EXPERIMENTAL PANCREATIC DIABETES II. THE BLOOD AND LIVER LIPIDSOF DOGS FED DURING TOTAL INSULIN DEPRIVATION1

THE OBSERVATION THAT the pancreas contains, besides insulin, a factor (or fac-tors) controlling lipid metabolism of blood and liver made necessary a reinves-tigation of the lipid changes that are to be ascribed to the absence of the anti-diabetic hormone per se. It was previously shown that no rise need occur in the cholesterol, phospholipids or fatty acids of the blood when depancreatized dogs re-ceive no insulin during the fasting state. Indeed, in those dogs in which a high lipid level had been established before cessation of insulin treatments, a fall in the concen-tration of alj lipid constituents followed the withdrawal of both food and insulin. The present study deals with the blood lipid changes resulting from insulin depriva-tion during nutritional states in which diets were fed containing a) raw pancreas and b) meat, but none of the glandular tissue.

LIPID METABOLISM IN EXPERIMENTAL PANCREATIC DIABETES I. BLOOD AND LIVER LIPIDS OF DOGS FASTED DURING TOTAL INSULIN DEPRIVATION1

THE OBSERVATION THAT the pancreas contains, besides insulin, a factor (or fac-tors) controlling lipid metabolism of blood and liver made necessary a reinves-tigation of the lipid changes that are to be ascribed to the absence of the anti-diabetic hormone per se. It was previously shown that no rise need occur in the cholesterol, phospholipids or fatty acids of the blood when depancreatized dogs re-ceive no insulin during the fasting state. Indeed, in those dogs in which a high lipid level had been established before cessation of insulin treatments, a fall in the concen-tration of alj lipid constituents followed the withdrawal of both food and insulin. The present study deals with the blood lipid changes resulting from insulin depriva-tion during nutritional states in which diets were fed containing a) raw pancreas and b) meat, but none of the glandular tissue.

THE PRESENT STATUS OF LIPOCAIC

The probability that the pancreas furnishes more than one internal secretion to the organism was suggested by the discovery of more than one type of cell in the islets of Langerhans. The evidence that insulin is elaborated by the beta cells of the islets is now fairly conclusive. The function of the alpha cells remains unknown. In 1924 Fisher 1 and Allan, Bowie, Macleod and Robinson 2 demonstrated that completely depancreatized dogs could not be maintained alive for long even though adequately treated with insulin. At death the most obvious change observed was an extensive fatty infiltration and degeneration in the liver. In one experiment, however, Fisher noted an extreme degree of arteriosclerosis of the aorta. The addition of raw pancreas to the diet was found by Macleod and his associates to prevent the development of these changes in the liver and to permit survival for long periods of time.

LIPOCAIC AND FATTY INFILTRATION OF THE LIVER IN PANCREATIC DIABETES

In 1924 Fisher1and Allan, Bowie, Macleod and Robinson2reported that completely depancreatized dogs adequately treated with insulin usually failed to survive more than two to three months. At autopsy the most prominent change observed was an extensive fatty infiltratration and degeneration in the liver. In general these findings have been widely confirmed. Occasional animals have been observed in which the fatty changes developed and death occurred in five to six weeks, while others have survived for six months to a year and still others have failed to show any evidence of disease of the liver and have survived for long periods with no supplementary treatment other than the insulin therapy. The latter constitute a small minority and will be discussed later. The addition of raw pancreas to the diet of the depancreatized dog was found by Allan, Bowie, Macleod and Robinson to prevent or relieve the fatty

Influence of Ingestion of Raw and Desiccated Pancreas Upon Blood Lipids During Infection.

It has been shown that there is a definite lowering of the levels for the plasma lipids at height of an acute infection as compared with the values obtained during convalescence.1 There is, however, a tendency for the lipid content of the blood plasma to rise very slowly and to remain below the normal range during the period of recovery as long as any infection is still present. This condition of the plasma lipids during an illness in the child has been found to be quite similar to the changes which have been observed by Chaikoff and Kaplan in the blood lipids of depancreatized dogs maintained with insulin.2, 3The depancreatized dogs developed a moderate decrease in blood fat, a small drop in the plasma phospholipid values, and a marked fall in the total cholesterol due almost entirely to a reduction in ester cholesterol to the point of disappearance from the blood in some of the animals. The free cholesterol content of the blood serum changed very little. When raw pancreas was included in all diets fed a...

ENLARGEMENT OF THE LIVER IN DIABETIC CHILDREN

In the preceding paper we 1 discussed the general characteristics of hepatomegaly as seen in 60 diabetic children possessing this complication. The present report is concerned with the results of treatment with three agents; raw pancreas, betaine hydrochloride and protamine insulin. METHODS All the children were kept under close observation, and most of them spent one or more weeks in the hospital during the period of study. For the greater part of the time, however, the patients were at home, because of the expense and undesirability of prolonged hospitalization. One must accept the fact that the care taken by the patients and their families as regards diet and insulin probably varied somewhat from time to time, so that strictly comparable conditions throughout cannot be claimed. It is most likely that during the periods of special medication, as with betaine and with protamine insulin, more care was given also to other

Hepatic lesions presumably secondary to pancreatic lithiasis and atrophy; report of two cases

Experimental and clinical evidence is cited which seems to demonstrate: (1) the occurrence of fatty degeneration of the liver when there is extensive destruction of the pancreas, (2) that the absence of the hormonal substance, lipocaic, may be the inciting factor for these changes in the liver, and (3) that there may be some therapeutic use for this preparation in certain clinical cases of pancreatic disease. If this is not available, the feeding of raw pancreas and diets high in lecithin is suggested. The possible relation of fatty change to the later development of cirrhosis invites speculation.

Action of Pancreatic Extract on Fatty Liver

Kaplan and Chaikoff1 have shown that the fatty infiltration of the liver in depancreatized insulin-treated dogs can be inhibited by the addition of raw pancreas to the usual diet. Dragstedt2 and his co-workers then showed that the active factor can be extracted from pancreas by the aid of alcohol. In conjunction with these investigations, we sought to answer the following two questions: (1) whether in normal rats the fat content of the liver can be influenced by a diet of pancreas ; and (2) whether a variation in the fat content of the liver is linked with a variation of the carbohydrate content.

Epinephrine Secretion in Animals with Experimental Diabetes

Rogoff and Ferrill1 have shown that the development and course of diabetes following total extirpation of the pancreas, in dogs, is not modified by reduction or suppression of epinephrine secretion, from the adrenal glands. Further, they observed that in depan-creatized dogs, not subjected to operations for interference with epinephrine secretion, a marked reduction in the epinephrine output may occur after various periods, under treatment with insulin on a constant diet.We are investigating the probable causes for this disturbance of the epinephrine secretion from the adrenals and have attempted to determine whether the following factors play a role: a, the diabetic state, b, a possible influence of insulin, c, integrity of the splanchnic innervation. This report is a summary of the results obtained by us in experiments on 39 dogs.Sixteen animals (Group 1) were totally pancreatectomized and kept on a diet consisting of 500 gm. boiled beef lung, 100 gm. cane sugar and 75 gm. fresh raw beef pancreas daily....

Mediterranean disease-thalassemia(Erythroblastic anemia of cooley): Associated pigment abnormalities simulating hemochromatosis

This disease is due to some racial, inherited defect which is responsiblefor the abnormalities of the hemopoictic tissues (of the order of pernicious anemia), the bone changes (of the order of acromegaly), and the pigment abnormalities (practically identical with hemochromatosis). This suggests a deficiency state which may be remediable when completely understood and gives adequate grounds for a variety of therapeutic tests. We record in detail the complete autopsy findings in three new cases of this disease and partial autopsy findings in two others. We believe the pigment deposits in these cases (simulating hemochromatosis) are as characteristic of this disease as are the recorded abnormalities of the hemopoietic system and bony skeleton. The anemia may be classified as microcytic and hypochromic. Macrocytosis and thinning of the cells occurred in two cases after splenectomy. In two cases (Cases 3 and 8) the total blood volume and the plasma volume were found to be normal, while the red cell volume was decreased. Wet preparations revealed marked fragmentation but no tendency to sickle. The following therapeutic measures, which we believe have been adequately tested, failed to modify the clinical picture: blood transfusions, plasma and cell extracts, primary or secondary anemia liver extracts, fetal liver extract, spleen extract, raw pancreas, adrenal cortex extract (cortin), estrogenic substance (progynon), vitamin B1 concentrate, iron, and copper. This disease is due to some racial, inherited defect which is responsiblefor the abnormalities of the hemopoictic tissues (of the order of pernicious anemia), the bone changes (of the order of acromegaly), and the pigment abnormalities (practically identical with hemochromatosis). This suggests a deficiency state which may be remediable when completely understood and gives adequate grounds for a variety of therapeutic tests. We record in detail the complete autopsy findings in three new cases of this disease and partial autopsy findings in two others. We believe the pigment deposits in these cases (simulating hemochromatosis) are as characteristic of this disease as are the recorded abnormalities of the hemopoietic system and bony skeleton. The anemia may be classified as microcytic and hypochromic. Macrocytosis and thinning of the cells occurred in two cases after splenectomy. In two cases (Cases 3 and 8) the total blood volume and the plasma volume were found to be normal, while the red cell volume was decreased. Wet preparations revealed marked fragmentation but no tendency to sickle. The following therapeutic measures, which we believe have been adequately tested, failed to modify the clinical picture: blood transfusions, plasma and cell extracts, primary or secondary anemia liver extracts, fetal liver extract, spleen extract, raw pancreas, adrenal cortex extract (cortin), estrogenic substance (progynon), vitamin B1 concentrate, iron, and copper.