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The effects of alloxan on the fetal rat pancreas

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The effects of alloxan on the fetal rat pancreas

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Content THE EFFECTS OF ALLOXAN ON THE FETAL RAT PANCREAS A Thesis Presented to the Faculty of the Department of Zoology University of Southern California In Partial Fulfillment of the Requirements for the Degree Master of Science by Melanio Y. Agdeppa January 1951 UMI Number: EP67186 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. Oissôftâliûn Publishing UMI EP67186 Published by ProQuest LLC (2014). Copyright in the Dissertation held by the Author. Microform Edition © ProQuest LLC. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code ProQuest LLC. 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106 - 1346 Z ' S I AXi>H This thesis, written by MELANIO Y. AODSPPA under the guidance of J^3.....Faculty Committee, and approved by a ll its members, has been presented to and accepted by the Council on Graduate Study and Research in partial fu lfill ment of the requirements fo r the degree of MASTER OF SCIENCE Dean Faculty Committee ' - T cJ X . ..... Chairman ...... F.M. BALDWIN The author acknowledges his indebtedness to Dr. Joseph A. Tuta, pathologist at Seaside Memorial Hospital of Long Beach, California, who interpreted the histological findings, and to Mr. Joseph Bamberger, Department of Zoology of the University of Southern California, who processed the photomicrographs. TABLE OF CONTENTS PAGE I. INTRODUCTION .......................... 1 II. HISTORICAL REVIER .................... 1 III. MATERIALS AND METHODS................ 11 IV. OBSERVATIONS.......................... 13 V. SUi.MARY AND CONCLUSIONS................ 14 LITERATURE CITED ............................. 16 INTRODUCTION Alloxan, a pyrimidine having the formula ---- H-N 0=0 \ I 0=C CsO 1 1 H-N __ C-0 has been used in the experimental production of diabetes mellitus in several laboratory animals. There is a selective action upon the beta cells in the islands of Langerhans. The purpose of this paper is to report the effect of alloxan on the fetal pancreas of the rat when the mother has received intravenously a diabetogenic dose of this drug. HISTORICAL REVIEW One of the early experiments on alloxan was done by Jacobs (1937) when he injected intravenously 70 mgs./Kg. in rabbits. He noticed a fall in blood sugar level in 3 to 4 hours. The animals showed convulsive states when the blood sugar level reached about 35 mgs. percent. There was a transient hyperglycemia preceding the fall in blood sugar. The convulsions and hypoglycemia were promptly relieved by the administration of glucose. Jacobs did not make any histological studies. Dunn, Sheehan and McLetchie (1943 b) studying the crush syndrome and mismatched blood transfusions. Injected uric acid into some rabbits and found selective lesions in the distal convoluted and collecting tubules. Using alloxan in place of uric acid, they noted that the animals died within the first day or so with symptoms not referable to renal disease, and it was in the course of these investigations that a lesion was found in the islands of Langerhans. Histological findings in one of the rabbits used showed that the acinar tissue appeared normal and some eosinophilic casts were present in the ducts. The islands of Langerhans were all abnormal; there was complete necrosis of the central cells in most of them, leaving only a ring or a crescent of living cells at the periphery. Goldner and Gomori (1943), produced alloxan diabetes in the dog. An injection of 100 mgs./Kg. resulted in death but produced typical diabetes without renal lesions. The main histological features found were a disappearance of the beta cells from the islands, profound vacuolation of the pancreatic duct epithelium, and fatty changes in the liver. Bailey and Bailey, in their preliminary report (1943) on the production of diabetes mellitus in rabbits by alloxan, found that 200 mgs./Kg. given intravenously gave an immediate transitory rise in blood sugar followed by hypoglycemia of several hours duration. If hypoglycemic death was prevented by repeated administration of dextrose, an apparently permanent state of hyperglycemia developed within 24 hours. Their histologic observations confirm the results of Dunn, Sheehan and McLetchie that the injury to the islands of Langerhans is produced by alloxan. This is probably the basis for the permanent hyperglycemia. The explanation for the hypoglycemic state is not absolutely clear at this time. According to Dunn, Sheehan and McLetchie, this hypoglycemia may result from a primary stimulation of the islands or it may be that the necrotic islands release a large amount of insulin. Hughes, Ware and Young (1944) state that it is due to the slow release of preformed insulin from dying cells of the islands of Langerhans ^ Ridout, Ham and Wrenshall (1944) claim that this is a process wherein the insulin content of the islands is leached from the dead cells into the blood stream. Kennedy and Lukens (1944) are also of the opinion that alloxan injury to the cells of the islands of Langerhans results in the liberation of insulin causing hypoglycemia. Gomori and Goldner (1943) injected alloxan into rats and using a special chrome hematoxylin and phloxine stain, observed nuclear pyknosis of the beta cells as early as 3 hours after injection. This pyknosis became more pronounced after 8 hours and shrinkage of the cytoplasm was evident. At 20 hours, the majority of the beta cells were greatly shrunken, and in some cases cell cords had disintegrated leaving only individual cells; in other cases the cords coalesced into an almost homogeneous mass, in which individual cells could not be recognized. On the second day, changes became more accentuated, and the beta cells began to lose granularity and staining properties, becoming pale bluish-gray remnants. Prom the third day on, these remnants disappeared very rapidly. On the fourth and fifth days, only occasional beta cells could be found. Agranular cells of an unidentifiable nature appeared in large nimbers occupying areas formerly occupied by necrotic beta cells. Uninjured peripheral alpha cells of the islet tissue exhibited considerable proliferation. By the fifth and sixth days, islets became free from debris, and special stains showed that they consisted of agranular and alpha cells only; beta cells were completely absent. Vacuolation of islet tissue was not seen at any stage of the diabetes. Mitoses were extremely rare and ducts and acinar parenchyma showed no change. Goldner and Gomori (1944 b) found that 50 mgs./Kg, of alloxan given in a single dose produced a sustained diabetes mellitus in dogs. One hundred mgs. or more per Kg. may be fatal or may cause a hyperglycemic-uremic syndrome terminating in death within 4 to 7 days. A dose of 25 mgs./Kg. gives no apparent symptoms in dogs. Histologically, the beta cells of the islands of Langerhans are degranulated and may disappear completely, the alpha cells appear normal, the small pancreatic ducts show vacuolizations, the kidneys show glycogen depositions, and fatty degeneration of the liver is found in later stages. Bio-assay of insulin in the pancreas of 2 of these dogs showed very low values. There seems to be no tendency to spontaneous recovery. Some dogs that survived for more than 2 months have remained diabetic. Carrasco-Formiguera (1944) also studied alloxan diabetes in dogs. He confirmed the production of pancreatic diabetes in dogs and also the followings alloxan can produce diabetes of varying degrees of severity; the diabetes, when very mild, may be spontaneously curable ; the initial blood sugar changes brought about in the dog by diabetogenic doses of alloxan are slower in their appearance and smaller in magnitude than those in the rabbit (Bailey and Bailey, 1943); the initial hyper glycemia begins later and lasts longer. The subsequent fall begins much later, and in these experiments never reached hypoglycemic levels. None of the three dogs that became diabetic required any antihypoglycemic treatment in order to be kept alive. In all three dogs that survived injections of alloxan for more than one day, diabetes, with hyperglycemia and glycosuria, was established 24 hours after the injection. Toxic reactions, other than those related to blood sugar changes such as emesis, depression, paresis and torpor, were observed in some cases. Two dogs injected v/ith 300 mgs./Kg. died in a very short period of time. A wide range of variations as to the individual reactiveness of dogs both to the toxic and to the diabetogenic dose of alloxan was also found by Carrasco-Formiguera. Brunschwig, Allen, Owens and Thornton (1944) administered alloxan as a chemotherapeutic agent to a patient with insulin-producing, islet-cell carcinoma with métastasés in the liver and exhibited attacks of hyper- insulinism increasing in frequency and severity. The rationale for alloxan therapy was that, since the radiosensitivity of tumors roughly parallels the radiosensitivity of normal tissues from which they arise, a chemical agent exerting specific noxions effects on normal pancreatic islet cells might influence favorably insulin-producing, islet-cell carcinoma. Temporary symptomatic relief was obtained for brief periods following each series of injections. This was demonstrated by a not abnormally low blood sugar level. Death, however. resulted from a complication at laparotomy. Alloxan did not cause necrosis of the malignant islet cells. Conn, Einerman and Buxton (1947) reported a case of a woman with pancreatic islet-cell tumor and hyper- insulinism. The patient was given a nine-day course of alloxan injections. At operation the tumor was found and removed. The islets of the pancreas proper were found to be severly damaged. Immediately on removal of the tumor typical diabetes mellitus developed. This experience suggests that the pancreatic islet tissue of human beings is sensitive to alloxan. Connus experience contradicts the repeatedly expressed opinion that human islet tissue is exceedingly resistant to the degenerative effects of alloxan. Goldner and Gomori (1944 c, Gomori 1945) have attempted to explain the action of alloxan on the pancreas. Evidence shows that alloxan affects the beta cells directly and does not act through the medium of disturbed blood sugar regulation. The initial hyper glycemia can be prevented by insulin, the following hypoglycemia by glucose injections, yet even then the beta cells were shrunken or had completely disappeared# These same authors studied further the mechanism of alloxan diabetes (1947) and concluded that the secondary alloxan hypoglycemia depends on the amount of 8 islet cell tissue present or of insulin available. This relationship between alloxan hypoglycemia and pancreatic insulin content does not hold true for every species and the absolute weight of the pancreas and the rate of insulin production may play a significant role. Lazarow (1946) has investigated the protective effect of glutathione and cysteine against alloxan diabetes in rats. He found that intravenous injections of large doses of glutathione or cysteine one to two minutes prior to injections of a diabetogenic dose of alloxan, completely protected rats from diabetes. Other amino acids, phosphate buffer and ascorbic acid gave no protection. When sulfhydryl compounds were given one minute after the alloxan injections, partial protection occurred, whereas when three or more minutes had elapsed there was no protection. It has been known for quite sometime that fetal and neonatal mortality is increased among infants born to himian diabetic mothers (Miller and Wilson 1943). There is a marked tendency for the human fetus of diabetic mothers to have an increased birth weight without evidence of a prolonged gestation period. Changes in the viscera and endocrine glands of some infants born to diabetic mothers have also been reported. These consist of cardiac enlargement (Miller and Wilson, 1943), increased glycogen content of the myocardium (Hurwitz and Irving, 1937; Miller, Johnson and Durlâcher, 1944), increased erythropoiesis in liver and other tissues (Miller et al. 1944), increased eosinophilia in the anterior hypophysis (Okkels and Brandstrupp, 1938; Miller and Wilson, 1943; Dubreuil and Anderodias, 1920; Helwig, 1940), and hyperplasia of gonads (Smith and Olney, 1938; Benner, 1941). In his studies on the effect of pregnancy complicated by alloxan diabetes on the fetuses of dogs, rabbits and rats. Miller (1947) found that diabetic pregnancies in rabbits resulted in many abortions, premature deliveries, still births, and the delivery of immature fetuses. About half of the diabetic pregnancies were full term. There was no evidence of an increased birth weight among the fetuses of diabetic rabbits. All of the pregnancies of the diabetic rats were full term resulting in the birth of healthy fetuses that had normal birth weights. The experiments with diabetic dogs were too few to be conclusive. There was only one abnormal pregnancy in the three that were studied. Alloxan did not have any ill effects on the fetuses. Davis, Pugo and Lawrence (1947), studying the effect's of alloxan on reproduction in the female rat. 10 found that permanent hyperglycemia resulted in an alteration of the normal estrus pattern, so that the intervals were greatly prolonged. Pregnancy progressed normally until about the 12th day following which the fetuses died and were slowly reabsorbed. Hie placentas were retained and were delivered at the end of the normal term. The adequate treatment of the alloxan diabetes by insulin resulted in normal pregnancies and live litters delivered at term. Friedgood and Miller (1945) found that in pregnant rats, alloxan given intravenously, passed through the placenta to the fetal circulation within 1 to 2 minutes. It does not produce permanent diabetes in the offspring. The blood sugar valves of the fetus parallels at a lower level that of the diabetic mothers until parturition. Koref, Fernandez and Te1chi (1946), claim that the alloxan diabetes in pregnant rabbits is also exhibited by the fetuses. Sinden and Longwell (1949) found that the estrus cycle ceased in alloxan diabetic female rats but was restored by the administration of insulin. Transient hyperglycemia did not interfere with reproduction and diabetes in the mother did not result in hyperglycemia in the offspring. MATERIALS AND METHODS The animals used in this investigation were white albino rats, U.S.C. Wistar strain of breeding age. A total of twenty-five female rats were numbered and weighed. The drug was purchased from the Eastman Kodak Company. One group of three female rats had their blood sugar levels determined by micromethod (Lauber and Mattice, 1944) before they were introduced to males in the breeding cage. Animals of this group were not given an injection of alloxan and were used as controls. These animals were allowed to go through pregnancy; the litters sacrificed at birth; their pancreases fixed in modified Bouin’s solution (Gomori 1941), embedded in paraffin, cut at 4 microns, and stained by the Gomori method (1941)# A second group of ten female rats were numbered and weighed. The initial blood sugar of each was determined after a twenty-four hour fast. A diabetogenic dose of alloxan from a freshly prepared 5 percent solution in water was injected through the tail vein. After 48 hours, blood sugar levels were determined by micromethod to see if they exhibited hyperglycemia. As soon as they were diabetic, they were introduced to males in the breeding cage. 12 Twelve female rats of a third group were treated the same way as the second group except that they did not receive any injection of alloxan until they were 16 or 17 days along in their gestation period. Within 24 to 48 hours after the injections of alloxan, blood sugar levels were determined to be sure they were hyperglycemic. This diabetic condition was maintained until parturition. The blood sugar levels of fasted rats varied from 90 to 160 mgs. percent. If an animal in this study showed a blood sugar level of 300 mgs. percent or higher it was considered hyperglycemic. As soon as a diabetic rat gave birth to a litter, two or three fetuses from this litter were sacrificed and the pancreatic tissues were taken for histological studies. The mother was also sacrificed at this time and its pancreas was taken for sectioning. This would give a basis for comparison of any changes taking place in the fetal pancreas. OBSERVATIONS The microscopic examination of the fetal pancreatic tissue of the control group shows the islands of Langerhans as isolated masses of cells scattered throughout the acinar portion of the organ. The beta cells which stain blue, show their granules clearly. Alpha cells are not seen. No litters were obtained from the second group of ten rats which were made diabetic before breeding. It is possible that pregnancy may have occurred in some of these animals but the fetuses probably resorbed. Alloxan definitely disturbs the estrus pattern in the rat (Davis, Pugo and Lawrence, 1947; Sinden and Longwell, 1949). The histological studies of the pancreatic tissues of litters from the third group of females rendered diabetic after 14 to 17 days of pregnancy showed a few islands of Langerhans scattered throughout the acinar portion of the organ. The beta cells exhibited their granules clearly. There was no evidence of pyknosis in the beta cells. There were some focal areas of interstitial edema. No alpha cells were seen. (See Pigs. 3 and 4, PI. 2. App.) The pancreatic tissues of the diabetic mothers showed the usual findings exhibited by animals susceptible to alloxan. These were degranulation of the 14 beta cells accompanied by pyknosis of nuclear material and loss of staining properties. Around the periphery of the islets were alpha cells which were not affected by alloxan. (See Figs., 1 and 2 App. ) SUMMARY AND CONCLUSIONS This study was undertaken to determine whether or not an alloxan-induced diabetic condition of pregnant rats during the latter part of pregnancy affected the pancreases of their fetuses. Histological studies of the fetal islands showed the beta cells which differentiated during intrauterine development to be unaffected. There is a possibility that by the time the alloxan has reached the fetal circulations from the maternal side, it is probably converted to other compounds which have no necrotizing effects on the fetal islet cells. No alpha cells were seen. This confirms the work of Hard (1944) who found that the alpha cells do not begin to differentiate until the second day of postnatal life. 15 I ë g % I g to § ë â 4^ ü c O © f i Ph © § 0 © CQ î > s 1 f i © - P > «H i > i rH © f J O d g o S f , 43 ë S > •H C Î3 ra bO O f i fi © 43 © 43 a 4-3 43 © <H *H O 0 5 (H f i , © f i 44 A ( d O bû ■ • f 3 >5 r a ra fi © t3 > O «H O rH iH © CQ T) bC S fi © A fi rî © O -P 43 44 p ; 44 43 © C d o ü © fi "r-3 f j ^ ^ • T O f U r a a j bO O rH Ü I —I I —J tH m a s f i cd ^ 43 T O Ü © Tj O O f i O © iH A rO r4 T O c d bO :: G 3 " o Pi 43 o d « O I —I to Ü3 C d 43 C d o 1 2 5 O lO cd 43 Cd T3 O îs; a s 43 Cd T3 O S 02 O to o to t f j o 03 1 —1 lO 02 1 —1 to to 00 to S o cd cd cd cd cd o lO lO 43 43 43 43 43 o rH 00 O c d cd cd cd o d rH co O to 'O 'O "0 tj X S lO 02 CD O 8 rH to O O O O O CD 03 to 5 2 ; a 1 2 5 % to 03 œ (M CD 03 œ rH Oi O rH co 03 03 CD O rH ' c M O rH î> 03 to O o co rH rH C O ë o 02 03 § O 02 g O S m S S 02 to lO CD O 00 02 02 02 02 02 02 02 02 LITERATURE CITED Bailey, C.C. and Bailey, O.T. 1943 Production (From Necrosis of Islets of Langerhans) of diabetes with alloxan. Preliminary report. J.A.M.A., 122, 1165-1166. Benner, M.C. 1941 Stimulation of gonads associated with hyperinsulinism in an infant. Arch. Path. 32, 818-824. Brunschwig. A., Allen, J.G., Owens, F.M., and Thornton, T.F. 1944 Alloxan in the treatment of insulin producing islet cell carcinoma of the pancreas. J.A.M.A. 124, 212. Carrasco-Forraiguera, R. 1944 Alloxan diabetes in dogs. J. Lab. and Clin. Med. 29, 510-517. Conn, Jerome W., Einerman, D.L. and Buxton, R.W. 1947 Effects of alloxan upon the human pancreas. J. Lab. and Clin. Med. 32^ 347-348. Davis, M. Edward, Pugo, Nicholas, and Lawrence, Kenneth G. 1947 The effect of alloxan diabetes on reproduction in the female rat. Proc. Soc. Exper. Biol, and Med. 66, 638-641. 17 Dubreuil, G. and Anderodias, J. 1920 Ilots de Langerhans géants chez un nouveau-né, issu de mere glycosurique♦ Corapt. rend. Soc. de biol. 2, 1490-1493. Dunn, J. Shaw and McLetchie, N.G.B. 1943 a Experimental alloxan diabetes in the rat. Lancet, 2, 384-387. Dunn, J. Shaw, Sheehan, S.H. and McLetchie, N.G.B. 1943 b Necrosis of the islets of Langerhans produced experimentally by steryl-quinoline and alloxan. Lancet, 484-487. Friedgood, G.E. and Miller, A.A. 1945 Alloxan in pregnant rats. Proc. Soc. Exper. Biol, and Med. 5^, 62. Goldner, M.G. and Gomori, G. 1943 Alloxan diabetes in dog. Endocrinology, 33, 297-308. _________ and 1944 a Mechanism of diabetogenic action of alloxan. Proc. Soc. Exper. Biol, and Med., 55, 73-75. ________ 9 and 1944 b Alloxan diabetes in dogs. J.A.M.A., 124, 802. 18 9 and _____ . 1944 c Mechanism of alloxan diabetes. Endocrinology, 241-248. • and 1947 Further studies on the mechsnisTn of alloxan diabetes, pancreatectomy and alloxan. Proc. Soc. Exper. Biol, and Med., 65, 18-21. Gomori, G. 1941 Observations with differential stains on human islets of Langerhans. J. Path., IV, 395- 405. 1945 Acute nature of alloxan damage. Proc. Soc. Exper. Biol, and Med., 5^, 232-233. Gomori, G. and Goldner, M.G. 1943 Production of diabetes mellitus in rats with alloxan. Proc. Soc. Exper. Biol, and Med., 54, 287-290. Hard, Walter L. 1944 The origin and differentiation of the alpha and beta cells in the pancreatic islets in the rat. Am. J. Anat., 75, 369-392. Helwig, E.B. 1940 Hypertrophy and hyperplasia of islands of Langerhans in infants born of diabetic mothers. Arch. Int. Med., 221-239. 19 Hughes, H., Ware, L.L. and Young, F.G. 1944 Diabetogenic action of alloxan. Lancet, 1, 148-150. Hurwitz, D. and Irving, P.C. 1937 Diabetes and pregnancy. Am. J. M. 8c., 194, 85-92. Jacobs, H.R. 1937 Hypoglycemic action of alloxan. Proc. Soc. Exper. Biol. and Med., 3^# 407-409. Kennedy, W.B. and Lukens, D.W. 1944 Observations on alloxan diabetes. Proc. Soc. Exper. Biol. and Med., 143-149. Koref, Oscar, Fernandez, L.V. and Telchi, Abraham G. 1946 Alloxan y compuestos afines en la diabetes experimental. Soc. Biol. de Bogota, ^ (3) 92-96. Lauber, Frances U. and Mattice, Marjorie R. 1944 Micromethod for blood glucose. J. Lab. and Clin. Med., 113-116. Lazarow, A* 1946 Protective effect of glutathione and cysteine against alloxan diabetes in the rat. Proc. Soc. Exper. Biol, and Med., 61, 441-447. 20 Miller, E.G. 1947 Effect of pregnancy complicated by alloxan diabetes on fetuses of dogs, rabbits and rats. Endocrinology, 251-258. Miller, H.C., Johnson, R.D. and Durlâcher, S.H. 1944 A comparison of newborn infants with erythroblastosis fetalis with those born to diabetic mothers. J. Pediat., 24, 603-615. Miller, E.G. and Wilson, H.M. 1943 Macrosomia, cardiac hypertrophy, erythroblastosis and hyperplasia of islands of Langerhans in infants born to diabetic mothers. J. Pediat., 23, 251-266. Okkels, H. and Brandstrup, E. 1938 Studies on the thyroid gland X, pancreas, hypophysis and thyroid in children of diabetic mothers. Acta. path, et microbiol. Scandinav., 15, 268-284. 2 pi. Ridout, J.H., Ham, A.W. and Wrenshall, G.A. 1944 The correlations of the insulin content and the histological picture of the pancreas at intervals after the administration of alloxan. Science, 100, 57-58. 21 Sinden, Jo Anne and Longwell, Bernard B. 1949 Effect of alloxan diabetes on fertility and gestation in the rat. Proc. Soc. Exper. Biol, and Med., 70 (4) 607-610. Smith, F.S. and Olney, M.D. 1938 Diabetes and pregnancy; observations on the offspring with a pathologic report. J. Pediat., 15, 772-786. PLATE I Photograph Number 1. Normal pancreatic islet tissue from an aciult rat. Goraori stain. The beta cells exhibit*blue granules in their cytoplasm; alpha cells red with this stain. B.C. ____ Beta Cell AL.C. Alpha Cell Photograph Number 2. An island from pancreas of a diabetic rat. Gomori stain. ^ N.B.G. ____ Necrotic Beta Cell. A.G. ____ Acinar Cells. Some beta cells are pyknotic, others are beginning to lose their granularity. The cells around the periphery of the islet are alpha cells which remain unaffected by alloxan. i B e % ^ * » » » Ir . *' , ( ' ; * • K - P - J : * &. - /' M.8:c. I k • w ' ■«t . 2 <v t_ AC 5Q>v- PLAIDE II Photograph Number 3. Normal fetal pancreatic Islet. All the cells seen are of the beta type. This litter was sacrificed right after birth so that no alpha cells are seen. Gomori stain. Photograph Number 4. Islet tissue from a litter, the mother of which was kept diabetic 48 hours before delivery. All the cells which are of the beta type show their granules clearly. No pyknosis or degranulation evident. No alpha cells present. Gomori stain. % I » - 1 S - '• 50fi % m % Ê t T ^ - ' S Ê Ê .

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Creator Agdeppa, Melanio Y. (author)

Core Title The effects of alloxan on the fetal rat pancreas

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Degree Master of Science

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