Exocrine Pancreatic Function in Juvenile Diabetics W. Domschke, MD, F. Tympner, MD, S. Domschke, MD, and L. Demling, MD
In 11 juvenile diabetics and 13 control subjects, the secretin-pancreozymin test was performed. Duodenal-volume losses were corrected by use of radioactive vitamin B~2 as marker substance. As compared to normal subjects, juvenile diabetics had significantly decreased pancreatic outputs of amylase, trypsin, chymotrypsin, and to a lesser degree, of bicarbonate. Clinical evidence of disease of the exocrine pancreas was missing. There was no discernible relationship between the abnormality of external pancreatic function and the duration of diabetes mellitus or the dose of insulin required. Possible factors that may be responsible for the exocrine deficiency of the pancreas in juvenile diabetics are discussed.
T h e r e is some evidence that exocrine-pancreatic function may be influenced by the pancreatic hormones, i n s u l i n a n d glucagon. G l u c a g o n has been demonstrated to inhibit external p a n creatic secretion in dogs (1) and m a n (2, 3), whereas insulin, as shown in rats (4-6), is said to favor pancreatic e n z y m e synthesis. W h e t h e r changes in external pancreatic secretion can occur in h u m a n diabetes mellitus has long been debated. Chey et al (7) reported a high incidence of decreased amylase secretion in juvenile diabetics; unfortunately, no other e n z y m e activity was determined. L~/hdevirta (8) found an impaired exocrine function of the pancreas from the reduced pancreatic uptake of selen o m e t h i o n i n e occurring in i n s u l i n - d e p e n d e n t diabetics. In patients with m a t u r i t y onset diabetes, however, n o r m a l external pancreatic secretion has repeatedly been shown (9, 10). In the present investigation, the exocrinepancreatic function in j u v e n i l e diabetics was studied by means of the s e c r e t i n - p a n c r e o z y m i n test, including i n t r a d u o d e n a l instillation of radioactive v i t a m i n Blz as volume m a r k e r (11). From the Department of Medicine, University of Erlangen-Nuremberg,Erlangen, West Germany. Address for reprint requests: Dr. W. Domschke, Department of Medicine, D-852 Erlangen, Krankenhausstrasse 12, West Germany.
Digestive Diseases, Vol. 20, No. 4 (April 1975)
Pancreatic secretion was expressed in terms of bicarbonate, amylase, trypsin, and chymotrypsin outputs. D e t e r m i n a t i o n both of amylase and proteases seemed m a n d a t o r y , as at least in alloxan-diabetic rats pancreatic e n z y m e activities may be dissociated (5).
M A T E R I A L S AND M E T H O D S This study comprised 11 juvenile diabetics (9 males, 2 females; their ages averaging 25 years; no family history of diabetes mellitus) and 13 healthy control subjects of comparable age. Patients with chronic pancreatitis, as established by endoscopic retrograde pancreaticography (12), were excluded from this investigation. All patients were studied at a time when their diabetes was under satisfactory control; patients required insulin doses ranging from 20-88 units of depot insulin (Farbwerke Hoechst AG, Frankfurt/ M.-Hoechst, West Germany). Two series of pancreatic secretory tests were performed on each patient: the first with the individual dose of depot insulin administered 24 hours before the test and the second 2 hours before the test. Each patient and subject gave informed consent. Pancreatic exocrine function was assessed with the aid of the secretin-pancreozymin test. Details of the technique have been fully described in a previous paper (11). In shorL after an overnight fast of subjects, a Lagerl/Sftube with an attached thin plastic tube (internal diameter, 1 mm) was-guided by x ray--positioned with the tip near the Treitz ligament. The LagerlSf tube was used for sampling of duodenal contents, and the plastic tube for continuous instillation of SSCo-labelled vitamin B12 (Radiochemical Centre, Amersham, United Kingdom).
309
DOMSCHKE ET AL
From recovery rates of the marker substance, the volumes of duodenal aspirates were corrected. Another tube was introduced into the stomach for collection of gastric secretions. After a 30-minute basal period, secretin (1 clinical unit-CU/kg) was injected intravenously, and the duodenal secretion aspirated for 1 hour. Then, for a further hour, duodenal juice was collected under continuous intravenous infusion of secretin (I CU/kg-hr) plus pancreozymin (1 Ivy dog unit--IDU/kg-hr). Seeretin and pancreozymin were obtained from the GIH Research Unit, Karolinska Institutet, Stockholm, Sweden. From determinations in the duodenal aspirates, pancreatic outputs of bicarbonate (secretin phase), amylase, trypsin, and chymotrypsin (secretin-pancreozymin phase) were calculated. Bicarbonate output was expressed as milliequivalents (mEq) secreted per hour; enzyme outputs were computed as kilounits (KU) produced per hour. Significant differences were evaluated statistically (13) by means of the Wileoxon-Mann-Whitney test (unpaired measurements) and the signed rank test developed by Wilcoxon (paired samples). The probability level of 5% (0.05) was used in deciding whether or not to reject the null hypothesis.
JUVENILE DIABETICS F
~ 20 t~ 70
t
I-"
~
BICARBONATE
~
AMYLASE
~
TRYPSIN
40 ~ 20
F xz 6 ~ 4 "~ 2 r 4 t~--. t ~ 2
CHYMOTRYPSIN DEPOTINSULIN 24h 2h BEFORETEST Fig 2. Exocrine-pancreatic function of juvenile diabetics when given their individual doses of insulin 24 hours or 2 hours before examination (mean • SD).
2O t~ ~" IO
BICARBONATE
'~176 ~ 20 s~f
RESULTS
~
AMYLASE
20 TRYPSIN
"~
~
CHYMOTRYPSIN
CONTROLSJUVENILE DIABETICS Fig 1. Pancreatic outputs of bicarbonate, amylase, and proteases in juvenile diabetics and controls (mean values • so). 310
Between j u v e n i l e diabetics (individual doses of insulin given 24 hours before e x a m i n a t i o n ) and controls, the s e c r e t i n - p a n c r e o z y m i n test revealed consistent differences in each of the parameters of exocrine-pancreatic function measured in this study (Figure 1). Especially amylase, trypsin, a n d chymotrypsin outputs were markedly reduced (P < 0.002) a m o u n t i n g only to about 40% of n o r m a l ; the slighter decrease in bicarbonate production was also significant statistically (P < 0.05). In j u v e n i l e diabetics ( J D ) and controls (C), duodenal volumes (ml; m e d i a n s and ranges) were significantly different following secretin plus p a n c r e o z y m i n ( J D : 216.3, 96.3-434.2; C: 332.3, 245.0-523.4; P = 0.02) but they were Digestive Diseases, Vol. 20, No. 4 (April 1975)
EXOCRINEPANCREATIC FUNCTION
cells than into cells remote from the islets (16). Pancreatic endocrine-exocrine interaction is further indicated by the fact that, in normal rat pancreas, zymogen granules are preferentially localized in the acini surrounding the endocrine islets, whereas granules are homogeneously distributed in pancreatic glands from alloxandiabetic animals (17). Finally, evidence has been provided that, in rat pancreas, insulin regulates amylase synthesis at the level of transcription (5), i.e., amylase messenger-ribonucleic acid can only be synthesized in the presence of insulin. All in all, the above data obtained from aniDISCUSSION mal experiments suggest that high local concenData from this study are in agreement with trations of insulin in the pancreas may facilitate previous observations indicating a decreased exocrine function in some way. According to pancreatic-amylase output in juvenile diabetics Henderson's hypothesis (18), the fact that islets without clinical evidence of disease of the exof Langerhans are scattered throughout the ocrine pancreas (7). The present investigation pancreas essentially contributes to regular complements that observation by showing that working of the exocrine part of the gland. Conpancreatic secretion rates of trypsin, chymosequently, the exocrine deficiency in juvenile trypsin, and bicarbonate are also significantly diabetics, as shown in this report, may be due, reduced. Our data were obtained with the aid of in part, to lack of the trophic effect of insulin. the secretin-pancreozymin test, including intraExocrine abnormality of the pancreas was indeduodenal instillation of radioactive vitamin B~2 pendent of whether individual doses of insulin as volume marker; this technique has been were given 24 hours or 2 hours before examproved to provide reproducible results in the ination, thus suggesting that high local levels of analysis of exocrine-pancreatic function (11). Decreased external pancreatic function in ju- insulin, as necessary for normal exocrine activvenile diabetics might be due, at least in part, to ity, cannot be reached by systemic therapy. arteriolar lesions in the diabetic pancreas, which may lead to pancreatic fibrosis and exACKNOWLEDGMENTS ocrine atrophy (14). In addition, it is possible Thanks are due to Mr. R. Neuwirth for his valuablehelp that high levels of glucagon, as shown in the in statistical analysis, and to Miss F. Sade for her expert blood of subjects with diabetes mellitus (15), are technical assistance. partly responsible for the depressed exocrinepancreatic function in this disease. REFERENCES Moreover, animal experiments have shown 1. Dyck WP, Rudick J, Hoexter B, Janowitz HD: trophic effects of insulin on acinar cells; there is Influence of glucagon on pancreatic exocrine seevidence that, in rats, insulin controls the pancretion. Gastroenterology 56:531-537, 1969 creatic synthesis of amylase by favoring the en2. Dyck WP, Texter EC, Lasater JM, Hightower try of glucose into acinar cells, and the biosynNC: Influence of glucagon on pancreatic exthesis of chymotrypsinogen by favoring the ocrine secretion in man. Gastroenterology entry of amino acids (4). Accordingly, in mouse 58:532-539, 1970 pancreas, 35S-methionine has been shown to 3. DiMagno EP, Go VLW, Summerskill WHJ: Intraluminal and postabsorptive effects of amino penetrate more readily into periinsular-acinar
not significantly different in the secretin phase (JD: 212.8, 96.0-286.5; C: 235.1, 130.6275.4). There was no discernible relation between the pattern of external pancreatic secretion and the duration of diabetes mellitus (ranging from 1 to 13 years), or dose of insulin required. Exocrine-pancreatic function in the diabetic group did not differ appreciably (P > 0.05) when the diabetics were given their individual doses of insulin 24 hours or 2 hours before examination (Figure 2).
Digestive Diseases, Vol. 20, No. 4 (April 1975)
311
DOMSCHKE ET AL
4.
5.
6.
7.
acids on pancreatic enzyme secretion. J Lab Clin Med 82:241-248, 1973 Palla JC, Ben Abdeljlil A, Desnuelle P: Effect of insulin on the rate of biosynthesis of some pancreatic enzymes. Gut 9:254, 1968 S61ing HD, Unger KO: The role of insulin in the regulation of a-amylase synthesis in the rat pancreas. E urop J Clin Invest 2:199-212, 1972 Couture Y, Dunnigan J, Morisset J: Stimulation of pancreatic amylase secretion and protein synthesis by insulin. Scand J Gastroenterol 7:257-263, 1972 Chey WY, Shay H, Shuman CR: External pancreatic secretion in diabetes mellitus. Ann Intern Med 59:812-821, 1963
8. L~ihdevirta J: Testing of exocrine function of pancreas in diabetes mellitus by use of 75Semethionine and of secretin. Acta Med Scand 182:345-351, 1967 9. Bartelheimer H, Ritter U: Das exkretorische Pankreas bei Diabetikern. Med Klin 55:700703, 1960 10. Peters N, Dick AP, Hales CN, Orrell DH, Sarner M: Exocrine and endocrine pancreatic function in diabetes mellitus and chronic pancreatitis. Gut 7:277-281, 1966
312
11. Tympner F, Domschke S, Domschke W, Classen M, Demling L: Reproducibility of the response to secretin and secretin plus pancreozymin in man. Scand J Gastroenterol 9:377-381, 1974 12. Classen M, Tympner F, Phillip J, Domschke S, Domschke W, Demling L: Retrograde ductography (ERP) and exoerine function of the pancreas in patients with pancreatitis. Gut, 1975 (In Press) 13. Snedecor GW, Cochran WG: Statistical Methods. Sixth edition. Ames, Iowa, Iowa State University Press, 1967 14. Warren S, Le Compte PM: The Pathology of Diabetes Mellitus. Philadelphia, Lea & Febiger, 1952 15. Unger RH, Aguilar-Parada E, Miiller WA, Eisentraut AM: Studies of pancreatic alpha cell function in normal and diabetic subjects. J Clin Invest 49:837-848, 1970 16. Hansson E: The formation of pancreatic juice proteins studied with labelled amino acids. Acta Physiol Scand 46 (Suppl 161):1-99, 1959 17. Kramer MF, Tan HT: The periinsular aeini of the pancreas of the rat. Z Zellforsch Mikrosk Ana 86:163-170, 1968 18. Henderson JR: Why are the islets of Langerhans? Lancet 2:469~470, 1969
Digestive Diseases, Vol. 20, No. 4 (April 1975)
In 11 juvenile diabetics and 13 control subjects, the secretin-pancreozymin test was performed. Duodenal-volume losses were corrected by use of radioactive vitamin B~2 as marker substance. As compared to normal subjects, juvenile diabetics had significantly decreased pancreatic outputs of amylase, trypsin, chymotrypsin, and to a lesser degree, of bicarbonate. Clinical evidence of disease of the exocrine pancreas was missing. There was no discernible relationship between the abnormality of external pancreatic function and the duration of diabetes mellitus or the dose of insulin required. Possible factors that may be responsible for the exocrine deficiency of the pancreas in juvenile diabetics are discussed.
T h e r e is some evidence that exocrine-pancreatic function may be influenced by the pancreatic hormones, i n s u l i n a n d glucagon. G l u c a g o n has been demonstrated to inhibit external p a n creatic secretion in dogs (1) and m a n (2, 3), whereas insulin, as shown in rats (4-6), is said to favor pancreatic e n z y m e synthesis. W h e t h e r changes in external pancreatic secretion can occur in h u m a n diabetes mellitus has long been debated. Chey et al (7) reported a high incidence of decreased amylase secretion in juvenile diabetics; unfortunately, no other e n z y m e activity was determined. L~/hdevirta (8) found an impaired exocrine function of the pancreas from the reduced pancreatic uptake of selen o m e t h i o n i n e occurring in i n s u l i n - d e p e n d e n t diabetics. In patients with m a t u r i t y onset diabetes, however, n o r m a l external pancreatic secretion has repeatedly been shown (9, 10). In the present investigation, the exocrinepancreatic function in j u v e n i l e diabetics was studied by means of the s e c r e t i n - p a n c r e o z y m i n test, including i n t r a d u o d e n a l instillation of radioactive v i t a m i n Blz as volume m a r k e r (11). From the Department of Medicine, University of Erlangen-Nuremberg,Erlangen, West Germany. Address for reprint requests: Dr. W. Domschke, Department of Medicine, D-852 Erlangen, Krankenhausstrasse 12, West Germany.
Digestive Diseases, Vol. 20, No. 4 (April 1975)
Pancreatic secretion was expressed in terms of bicarbonate, amylase, trypsin, and chymotrypsin outputs. D e t e r m i n a t i o n both of amylase and proteases seemed m a n d a t o r y , as at least in alloxan-diabetic rats pancreatic e n z y m e activities may be dissociated (5).
M A T E R I A L S AND M E T H O D S This study comprised 11 juvenile diabetics (9 males, 2 females; their ages averaging 25 years; no family history of diabetes mellitus) and 13 healthy control subjects of comparable age. Patients with chronic pancreatitis, as established by endoscopic retrograde pancreaticography (12), were excluded from this investigation. All patients were studied at a time when their diabetes was under satisfactory control; patients required insulin doses ranging from 20-88 units of depot insulin (Farbwerke Hoechst AG, Frankfurt/ M.-Hoechst, West Germany). Two series of pancreatic secretory tests were performed on each patient: the first with the individual dose of depot insulin administered 24 hours before the test and the second 2 hours before the test. Each patient and subject gave informed consent. Pancreatic exocrine function was assessed with the aid of the secretin-pancreozymin test. Details of the technique have been fully described in a previous paper (11). In shorL after an overnight fast of subjects, a Lagerl/Sftube with an attached thin plastic tube (internal diameter, 1 mm) was-guided by x ray--positioned with the tip near the Treitz ligament. The LagerlSf tube was used for sampling of duodenal contents, and the plastic tube for continuous instillation of SSCo-labelled vitamin B12 (Radiochemical Centre, Amersham, United Kingdom).
309
DOMSCHKE ET AL
From recovery rates of the marker substance, the volumes of duodenal aspirates were corrected. Another tube was introduced into the stomach for collection of gastric secretions. After a 30-minute basal period, secretin (1 clinical unit-CU/kg) was injected intravenously, and the duodenal secretion aspirated for 1 hour. Then, for a further hour, duodenal juice was collected under continuous intravenous infusion of secretin (I CU/kg-hr) plus pancreozymin (1 Ivy dog unit--IDU/kg-hr). Seeretin and pancreozymin were obtained from the GIH Research Unit, Karolinska Institutet, Stockholm, Sweden. From determinations in the duodenal aspirates, pancreatic outputs of bicarbonate (secretin phase), amylase, trypsin, and chymotrypsin (secretin-pancreozymin phase) were calculated. Bicarbonate output was expressed as milliequivalents (mEq) secreted per hour; enzyme outputs were computed as kilounits (KU) produced per hour. Significant differences were evaluated statistically (13) by means of the Wileoxon-Mann-Whitney test (unpaired measurements) and the signed rank test developed by Wilcoxon (paired samples). The probability level of 5% (0.05) was used in deciding whether or not to reject the null hypothesis.
JUVENILE DIABETICS F
~ 20 t~ 70
t
I-"
~
BICARBONATE
~
AMYLASE
~
TRYPSIN
40 ~ 20
F xz 6 ~ 4 "~ 2 r 4 t~--. t ~ 2
CHYMOTRYPSIN DEPOTINSULIN 24h 2h BEFORETEST Fig 2. Exocrine-pancreatic function of juvenile diabetics when given their individual doses of insulin 24 hours or 2 hours before examination (mean • SD).
2O t~ ~" IO
BICARBONATE
'~176 ~ 20 s~f
RESULTS
~
AMYLASE
20 TRYPSIN
"~
~
CHYMOTRYPSIN
CONTROLSJUVENILE DIABETICS Fig 1. Pancreatic outputs of bicarbonate, amylase, and proteases in juvenile diabetics and controls (mean values • so). 310
Between j u v e n i l e diabetics (individual doses of insulin given 24 hours before e x a m i n a t i o n ) and controls, the s e c r e t i n - p a n c r e o z y m i n test revealed consistent differences in each of the parameters of exocrine-pancreatic function measured in this study (Figure 1). Especially amylase, trypsin, a n d chymotrypsin outputs were markedly reduced (P < 0.002) a m o u n t i n g only to about 40% of n o r m a l ; the slighter decrease in bicarbonate production was also significant statistically (P < 0.05). In j u v e n i l e diabetics ( J D ) and controls (C), duodenal volumes (ml; m e d i a n s and ranges) were significantly different following secretin plus p a n c r e o z y m i n ( J D : 216.3, 96.3-434.2; C: 332.3, 245.0-523.4; P = 0.02) but they were Digestive Diseases, Vol. 20, No. 4 (April 1975)
EXOCRINEPANCREATIC FUNCTION
cells than into cells remote from the islets (16). Pancreatic endocrine-exocrine interaction is further indicated by the fact that, in normal rat pancreas, zymogen granules are preferentially localized in the acini surrounding the endocrine islets, whereas granules are homogeneously distributed in pancreatic glands from alloxandiabetic animals (17). Finally, evidence has been provided that, in rat pancreas, insulin regulates amylase synthesis at the level of transcription (5), i.e., amylase messenger-ribonucleic acid can only be synthesized in the presence of insulin. All in all, the above data obtained from aniDISCUSSION mal experiments suggest that high local concenData from this study are in agreement with trations of insulin in the pancreas may facilitate previous observations indicating a decreased exocrine function in some way. According to pancreatic-amylase output in juvenile diabetics Henderson's hypothesis (18), the fact that islets without clinical evidence of disease of the exof Langerhans are scattered throughout the ocrine pancreas (7). The present investigation pancreas essentially contributes to regular complements that observation by showing that working of the exocrine part of the gland. Conpancreatic secretion rates of trypsin, chymosequently, the exocrine deficiency in juvenile trypsin, and bicarbonate are also significantly diabetics, as shown in this report, may be due, reduced. Our data were obtained with the aid of in part, to lack of the trophic effect of insulin. the secretin-pancreozymin test, including intraExocrine abnormality of the pancreas was indeduodenal instillation of radioactive vitamin B~2 pendent of whether individual doses of insulin as volume marker; this technique has been were given 24 hours or 2 hours before examproved to provide reproducible results in the ination, thus suggesting that high local levels of analysis of exocrine-pancreatic function (11). Decreased external pancreatic function in ju- insulin, as necessary for normal exocrine activvenile diabetics might be due, at least in part, to ity, cannot be reached by systemic therapy. arteriolar lesions in the diabetic pancreas, which may lead to pancreatic fibrosis and exACKNOWLEDGMENTS ocrine atrophy (14). In addition, it is possible Thanks are due to Mr. R. Neuwirth for his valuablehelp that high levels of glucagon, as shown in the in statistical analysis, and to Miss F. Sade for her expert blood of subjects with diabetes mellitus (15), are technical assistance. partly responsible for the depressed exocrinepancreatic function in this disease. REFERENCES Moreover, animal experiments have shown 1. Dyck WP, Rudick J, Hoexter B, Janowitz HD: trophic effects of insulin on acinar cells; there is Influence of glucagon on pancreatic exocrine seevidence that, in rats, insulin controls the pancretion. Gastroenterology 56:531-537, 1969 creatic synthesis of amylase by favoring the en2. Dyck WP, Texter EC, Lasater JM, Hightower try of glucose into acinar cells, and the biosynNC: Influence of glucagon on pancreatic exthesis of chymotrypsinogen by favoring the ocrine secretion in man. Gastroenterology entry of amino acids (4). Accordingly, in mouse 58:532-539, 1970 pancreas, 35S-methionine has been shown to 3. DiMagno EP, Go VLW, Summerskill WHJ: Intraluminal and postabsorptive effects of amino penetrate more readily into periinsular-acinar
not significantly different in the secretin phase (JD: 212.8, 96.0-286.5; C: 235.1, 130.6275.4). There was no discernible relation between the pattern of external pancreatic secretion and the duration of diabetes mellitus (ranging from 1 to 13 years), or dose of insulin required. Exocrine-pancreatic function in the diabetic group did not differ appreciably (P > 0.05) when the diabetics were given their individual doses of insulin 24 hours or 2 hours before examination (Figure 2).
Digestive Diseases, Vol. 20, No. 4 (April 1975)
311
DOMSCHKE ET AL
4.
5.
6.
7.
acids on pancreatic enzyme secretion. J Lab Clin Med 82:241-248, 1973 Palla JC, Ben Abdeljlil A, Desnuelle P: Effect of insulin on the rate of biosynthesis of some pancreatic enzymes. Gut 9:254, 1968 S61ing HD, Unger KO: The role of insulin in the regulation of a-amylase synthesis in the rat pancreas. E urop J Clin Invest 2:199-212, 1972 Couture Y, Dunnigan J, Morisset J: Stimulation of pancreatic amylase secretion and protein synthesis by insulin. Scand J Gastroenterol 7:257-263, 1972 Chey WY, Shay H, Shuman CR: External pancreatic secretion in diabetes mellitus. Ann Intern Med 59:812-821, 1963
8. L~ihdevirta J: Testing of exocrine function of pancreas in diabetes mellitus by use of 75Semethionine and of secretin. Acta Med Scand 182:345-351, 1967 9. Bartelheimer H, Ritter U: Das exkretorische Pankreas bei Diabetikern. Med Klin 55:700703, 1960 10. Peters N, Dick AP, Hales CN, Orrell DH, Sarner M: Exocrine and endocrine pancreatic function in diabetes mellitus and chronic pancreatitis. Gut 7:277-281, 1966
312
11. Tympner F, Domschke S, Domschke W, Classen M, Demling L: Reproducibility of the response to secretin and secretin plus pancreozymin in man. Scand J Gastroenterol 9:377-381, 1974 12. Classen M, Tympner F, Phillip J, Domschke S, Domschke W, Demling L: Retrograde ductography (ERP) and exoerine function of the pancreas in patients with pancreatitis. Gut, 1975 (In Press) 13. Snedecor GW, Cochran WG: Statistical Methods. Sixth edition. Ames, Iowa, Iowa State University Press, 1967 14. Warren S, Le Compte PM: The Pathology of Diabetes Mellitus. Philadelphia, Lea & Febiger, 1952 15. Unger RH, Aguilar-Parada E, Miiller WA, Eisentraut AM: Studies of pancreatic alpha cell function in normal and diabetic subjects. J Clin Invest 49:837-848, 1970 16. Hansson E: The formation of pancreatic juice proteins studied with labelled amino acids. Acta Physiol Scand 46 (Suppl 161):1-99, 1959 17. Kramer MF, Tan HT: The periinsular aeini of the pancreas of the rat. Z Zellforsch Mikrosk Ana 86:163-170, 1968 18. Henderson JR: Why are the islets of Langerhans? Lancet 2:469~470, 1969
Digestive Diseases, Vol. 20, No. 4 (April 1975)
