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Pancreatic function after normothermic ischemia
Pancreatic Function after Normothermic Ischemia II. Cadaveric Transplantation F. B. CERRA, MD, Chicago, Illinois
J. R. ADAMS, MD, Chicago, Illinois D. E. EGGERT, MD, Chicago, Illinois
J. B. EILERT, MD, Chicago, Illinois J. J. BERGAN, MD, Chicago, Illinois
Although transplantation of the pancreas is a limited clinical reality, the ability of this organ to withstand normothermic ischemia remains poorly defined {1,2]. Several models, each with its inherent liabilities, have been utilized in studying this problem. Reversible occlusion of pancreatic blood supply to the whole gland was found to be unreliable [2]. Preservation of an isolated portion of gland with a blood supply which is easily occluded and reopened demands that partial pancreatectomy be performed. Studies carried out in ex vivo perfusion preparations introduce a host of artificial factors and deny the opportunity to observe prolonged gland function [3]. Cadaveric transplantation provides total ischemia and exactly duplicates the anticipated clinical situation. This study was designed to investigate normothermic cadaveric ischemia and transplantation so that tolerable ischemia limits of the pancreas could be ascertained. Material and Methods
Donor Preparation. Thirty-four unselected mongrel dogs were used as donors. After administration of anesthesia (Nembutalw 30 mg per kg), sodium heparin (3,500 units) was injected intravenously and the dog was sacrificed by hemorrhage. The pancreas was ischemic for one, two, or three hours, For removal, the abdomen was opened in the midline, and the pancreas exposed. The splenic artery and vein were ligated and divided distal to their pancreatic branches, and the celiac trunk was prepared for anastomosis. The portal vein was skeletonized, and the hepatic branches of the celiac axis ligated. With the use of traction and sharp dissection, the pancreas was separated from the duodenum. (Figure 1.) Recipient Preparation. After pancreatectomy and documentation of diabetes, thirty-four dogs were preFrom the Department of Surgery, Northwestern University Medical School, 303 East Chicago Avenue. Chicago, Illinois 60611. This work was supported by a grant from the John A. Hartford Foundation, Inc. Volume 120. December 1970
pared as recipients for the pancreas by the method previously described [.n The allograft was removed after its cadaveric normothermic ischemic interval, was flushed with normal saline solution, and its vessels were tailored for anastomosis. The celiac artery of the graft was placed end to side to the recipient aorta and the portal vein end to side to the inferior vena cava. (Figure 2.) Dogs in group I received a pancreas with one hour of ischemia. Those in group II received a gland with two hours of ischemia, and those in group III, a gland with three or more hours of ischemia. Blood samples were drawn for daily determination of glucose, amylase, and radioimmune assay for insulin. On day five, intravenous glucose tolerance tests were performed on eight dogs. Animals were observed until death or until hyperglycemia was recorded on two successive days. No immune suppression was employed. Results
Although grafts subjected to two and more hours of ischemia were pale, flaccid, and dusky prior to transplantation, they assumed nearly normal appearance upon revascularization. Grafts with one hour of ischemia appeared normal at all times. Data relative to total transplants and functioning glands are summarized in Table r. Group I. Seventeen transplants were performed using glands with one hour of normothermic ischemia. Eleven functioned well. Six experiments were unsatisfactory because of death from respiratory infection (two animals) and venous outflow obstruction with or without pancreatitis (four animals). Of eleven animals receiving the pancreatic transplant, two were normoglycemic until death and nine demonstrated rejection of the gland on days eight and eleven. Fasting immunoreactive insulin values in this group were less than 2 microunits per ml prior to transplantation. A precipitous rise occurred in the first twenty-four hours after grafting, which was followed by a gradual decrease during the observa693
,qerra et al
.. ,..,."
Figure 2. The transplanted pancreas was placed retroperi· toneally and vascularized by conventional anastomoses as illustrated.
Cadaver Pancreatic Function after Normothermic Ischemia
TABLE I
Ischemia Time
Total Transplants
Functional Glands
17 12
11 4
5
1
1 hour 2 hours 3 or more hours
TABLE II
Dog Number 2105 2042 2058 2099 2065 2062 2005 2008 694
Insulin Washout from Pancreas with Two Hours of Ischemia Serum Insulin after Pancreatectomy 2.0 2.0 2.0 2.0 2.0 2.8 3.8
2.5
Serum Insulin afterTransplant
32.5 2.4
22.7 30.8 21.8 20.0 >100 52
tion period to values three times normal. This plasma IRI level was not consonant with the fasting serum glucose levels. (Figure 3.) Glucose tolerance tests on day five (Figure 4) showed a diminished response to the glucose load. No insulin delay was noted, but insulin output was lower than that seen in nonischemic transplants. The serum amylase response (Figure 5) of these glands with one hour ischemia and subjected to the trauma of transplantation was similar to that previously reported [5]. The post-transplant rise in serum amylase was profound and sustained. This response curve was much like that seen in pancreatic duct ligation in nontransplanted glands [6]. Amylase levels decreased coincidental with the acinar and parenchymal destruction of rejection. Group 11. Twelve dogs received a pancreas exposed to two hours of ischemia. Eight of the dogs: in this group were hyperglycemic on the first day after transplantation. Serum glucose values continued to increase until death. Seven of the deaths in this group were associated with respiratory infection, sepsis, or pulmonary embolism. Although one transplant was a technical failure, the remaining four preserved normoglycemia until death. Three of these animals died of respiratory infection on day five, and one died during rejection on day fifteen. Thus, only four of twelve transplants functioned well despite two hours of normothermic ischemia. Plasma insulin values in animals receiving a pancreas subj ected to two hours of ischemia were similar to those of group I. The characteristic pattern was of initial washout of gland insulin followed by decreasing values until death of the animal or rejection. (Table II.) Lack of prolonged recipient survival precluded glucose tolerance testing. Group III. Five animals received a pancreas which was ischemic for three hours or longer. One of these glands exhibited normal function and appeared normal on histologic examination when it was removed on day three. None of the other glands in this group showed satisfactory function although a variable amount of islet activity was present for three days in each. Comments
Experience from a number of laboratories has shown that the pancreas is a hardy gland which resists well the trauma and ischemia of conventional transplantation. Ischemia time necessitated by excision of the gland in the donor and vascular anastomosis in the recipient usually varies from ten to thirty minutes. Normal function is to be expected after this amount of normothermic ischemia The American Journal of Surgery
Pancreatic Function after Normothermic Ischemia 360 330 300 270 240 210 a! 180 ~ 150 .. 120
a~
90 60 30
60 55 50 45 40
,, I
I I I
INSULIN
,
GLUCOSE
I
I
35 Insuton 30 pU/ml 25 20 15 10
5 NOIlIlAL INSULIN RANGE
tl2345678910
Time In Days Figure 3. Plasma insulin values rose dramatically after transplantation of a gland sUbjected to one hour of ischemia. Hypoglycemia was not proportionate, however. TRANSPLANT
os'!
r ..
~ <;
220 200 180 160 140 120 100
120 100 00 80 70 60 Insulin 50 }lUI ml
80 60
40 30
40 20
20 10 oL - ; " - - -.........---.,;+----,.---,"--' 0 o 30 60 90 120
-----------, INSULIN
•
hill/itt I.~ GI._
Time in Minutes
Figure 4. The glucose tolerance test results are represented graphically. showing a diminished but adequate response by the pancreas ischemic for one hour.
6000 5600 5200 4800 4400 4000 ~ 3600 ~ 3200 2800 12400 .. 2000
j
1600 1200 800 400
o iii iii j f i i ~ TRAlISItUNT
Time ,n Day.
Figure 5. The high amylase values obtained after transplantation of a pancreas ischemic for one hour were indicative of persIsting acinar function until early rejection supervened.
even though perfusion, cooling, and other manipulation is not practiced. Similarly, after one hour of normothermic ischemia, the transplanted pancreas with duct ligated is able to maintain normoglycemia in the dog with no immune suppression until rejection occurs. Although glucose tolerance testing shows that the gland is able to respond to a glucose load, the ischemic and transplanted gland does not function normally. Its response to glucose challenge is sluggish and diminished as compared Volume 120. December 1970
to the normal. This is a logical response if one con-. siders the degree of ischemia which is produced. It is interesting to speculate whether or not endocrine function would improve after such an ischemic insult. There is no suggestion in this study that such, improvement occurs in the nonimmune modified animals but of course the ultimate answer awaits effective long-term control of rejection. In all three of the ischemia groups, an abnormally high level of plasma insulin was found after transplantation, a phenomenon which remains unexplained. However, the observation is consistent with the values found by a number of other inves-' tigators [7-9]. It has been thought in the past that post-transplant hyperinsulinemia was caused by bypass of hepatic insulinase by the heterotopic gland. However, the work of Starzl et al [10,11] and of Waddell and Sussman [12] shows that elevated plasma insulin is not caused by pancreatic blood reaching the systemic circulation rather than the portal circulation. More likely, the phenomenon of hyperinsulinemia is the result of islet damage from ischemia during the transplantation. This manifests itself as insulin washout immediately after revascularization of the gland in the recipient. The effects of transplantation ischemia seem to be persistent for some days after transplantation. They are similar to those of the in vivo ischemia studies previously reported. from this laboratory [2]. Later, the ischemia of the rejection process may contribute additional insulin release just prior to irreversible islet cell damage and ultimate hypoinsulinemia. Animals receiving pancreatic transplants under cover of immunosuppressive drugs show a prolonged period of plasma hyperinsulinemia [7,8]. -This may be caused by a smoldering rejection process. It is possible that the abnormally high level of insulin released by the islet cells would be of considerable duration if chronic rejection persisted. The paradoxical phenomenon of ischemia-induced insulin release can be explained. In the normal pancreatic beta cell, proinsulin is converted to insulin in the Golgi complex or in a stage intermediate between the endoplasmic reticulum and the Golgi, Insulin is stored in active form in the beta cell granules which are released by the simple process of emiocytosis. The beta cells are stimulated by hyperglycemia, after which the granules move to the surface of the cell where the membranous sacs enclosing the granules fuse to the plasma membrane. Rupture of this common wall causes release of the granule into the extracellular space where it undergoes immediate dissolution. Ischemia may act upon the plasma membrane of beta cells causing increased permeability to intra695
Cerra et al
cellular granules and their content of active insulin. The ischemia-damaged cell then may remain viable with a persistently permeable cell wall. If so, the beta cell would act in a fashion similar to intestinal mucosal cells which release potassium ion in response to ischemia and demonstrate increased cellular permeability after such trauma. Summary
Thirty-four cadaver pancreatic transplants were performed utilizing controlled ischemia times of one, two, and three or more hours. Although occasional function followed prolonged ischemia, normothermic ischemia tolerance of the pancreas appears to be about one hour. A paradoxical phenomenon of insulin washout was observed in all instances of revascularization after ischemia. Such insulin washout was not proportionate to duration of ischemia. References 1. Lillehei RC, et al: Pancreatico-duodenal allotransplanta_ tion. Ann Surg 172: 405, 1970. 2. Binder PS, Heiskell CA, Adams JR, Cerra FB, Eilert JB, Bergan JJ: Pancreatic function following normother-
696
3.
4. 5. 6. 7. 8. 9. 10.
11.
12.
mic ischemia. I. In vivo ischemia. Amer J Surg 120: 687,1970. Bergan JJ, Teixeira ED, Conn J Jr, Haid SP: Ex vivo pancreas perfusion. Organ Perfusion and Preservation (Norman, JC, ed). New York, Appleton-Century-Crofts, 1968. Bergan JJ, Hoehn JG, Porter N, Dry L: Total pancreatic allografts in pancreatectomized dogs. Arch Surg 90: 521, 1965. Teixeira ED, Bergan JJ: Auxiliary pancreas allografting. Arch Surg 95: 65, 1967. Ivy AC: Certain aspects of the applied physiology of external pancreatic secretion. Amer J Digest 3: 677, 1936. Ota K, Mori S, Inou T, Kanazawa Y, Kuzuya T: Endocrine function of the pancreatic allograft. Endocrinology 82: 731, 1968. Huguet C, Daloze P, Orcel L, Sussman KE: Endocrine function of pancreatic homotransplants in dogs. Arch Surg 98: 375, 1969. Teixeira ED, Sharkey E, Colwell J, Bergan JJ: Insulin and glucose levels following pancreas allografting. Surg Forum 17: 205,1966. Starzl TE, Scanlan WA, Yanof HM, Thornton FH, Wendel RM, Stearn B, Lazarus RE, McAllister W, Shoemaker WC: A comparison of hypoglycemic effect of insulin with systemic venous and portal venous administration. J Surg Res 3: 293, 1963. Starzl TE, Marchioro TL, Sexton AW, Illingworth B, Wad· dell WR, Faris TO, Herrmann TJ: The effect of portacaval transposition on carbohydrate metabolism: Experimental and clinical Observations. Surgery 57: 687, 1965. Waddell WR, Sussman KE: Plasma insulin after diversion of portal and pancreatic venous blood to vena cava. J Appl Physiol 22: 808, 1967.
The American Journal of Surgery
J. R. ADAMS, MD, Chicago, Illinois D. E. EGGERT, MD, Chicago, Illinois
J. B. EILERT, MD, Chicago, Illinois J. J. BERGAN, MD, Chicago, Illinois
Although transplantation of the pancreas is a limited clinical reality, the ability of this organ to withstand normothermic ischemia remains poorly defined {1,2]. Several models, each with its inherent liabilities, have been utilized in studying this problem. Reversible occlusion of pancreatic blood supply to the whole gland was found to be unreliable [2]. Preservation of an isolated portion of gland with a blood supply which is easily occluded and reopened demands that partial pancreatectomy be performed. Studies carried out in ex vivo perfusion preparations introduce a host of artificial factors and deny the opportunity to observe prolonged gland function [3]. Cadaveric transplantation provides total ischemia and exactly duplicates the anticipated clinical situation. This study was designed to investigate normothermic cadaveric ischemia and transplantation so that tolerable ischemia limits of the pancreas could be ascertained. Material and Methods
Donor Preparation. Thirty-four unselected mongrel dogs were used as donors. After administration of anesthesia (Nembutalw 30 mg per kg), sodium heparin (3,500 units) was injected intravenously and the dog was sacrificed by hemorrhage. The pancreas was ischemic for one, two, or three hours, For removal, the abdomen was opened in the midline, and the pancreas exposed. The splenic artery and vein were ligated and divided distal to their pancreatic branches, and the celiac trunk was prepared for anastomosis. The portal vein was skeletonized, and the hepatic branches of the celiac axis ligated. With the use of traction and sharp dissection, the pancreas was separated from the duodenum. (Figure 1.) Recipient Preparation. After pancreatectomy and documentation of diabetes, thirty-four dogs were preFrom the Department of Surgery, Northwestern University Medical School, 303 East Chicago Avenue. Chicago, Illinois 60611. This work was supported by a grant from the John A. Hartford Foundation, Inc. Volume 120. December 1970
pared as recipients for the pancreas by the method previously described [.n The allograft was removed after its cadaveric normothermic ischemic interval, was flushed with normal saline solution, and its vessels were tailored for anastomosis. The celiac artery of the graft was placed end to side to the recipient aorta and the portal vein end to side to the inferior vena cava. (Figure 2.) Dogs in group I received a pancreas with one hour of ischemia. Those in group II received a gland with two hours of ischemia, and those in group III, a gland with three or more hours of ischemia. Blood samples were drawn for daily determination of glucose, amylase, and radioimmune assay for insulin. On day five, intravenous glucose tolerance tests were performed on eight dogs. Animals were observed until death or until hyperglycemia was recorded on two successive days. No immune suppression was employed. Results
Although grafts subjected to two and more hours of ischemia were pale, flaccid, and dusky prior to transplantation, they assumed nearly normal appearance upon revascularization. Grafts with one hour of ischemia appeared normal at all times. Data relative to total transplants and functioning glands are summarized in Table r. Group I. Seventeen transplants were performed using glands with one hour of normothermic ischemia. Eleven functioned well. Six experiments were unsatisfactory because of death from respiratory infection (two animals) and venous outflow obstruction with or without pancreatitis (four animals). Of eleven animals receiving the pancreatic transplant, two were normoglycemic until death and nine demonstrated rejection of the gland on days eight and eleven. Fasting immunoreactive insulin values in this group were less than 2 microunits per ml prior to transplantation. A precipitous rise occurred in the first twenty-four hours after grafting, which was followed by a gradual decrease during the observa693
,qerra et al
.. ,..,."
Figure 2. The transplanted pancreas was placed retroperi· toneally and vascularized by conventional anastomoses as illustrated.
Cadaver Pancreatic Function after Normothermic Ischemia
TABLE I
Ischemia Time
Total Transplants
Functional Glands
17 12
11 4
5
1
1 hour 2 hours 3 or more hours
TABLE II
Dog Number 2105 2042 2058 2099 2065 2062 2005 2008 694
Insulin Washout from Pancreas with Two Hours of Ischemia Serum Insulin after Pancreatectomy 2.0 2.0 2.0 2.0 2.0 2.8 3.8
2.5
Serum Insulin afterTransplant
32.5 2.4
22.7 30.8 21.8 20.0 >100 52
tion period to values three times normal. This plasma IRI level was not consonant with the fasting serum glucose levels. (Figure 3.) Glucose tolerance tests on day five (Figure 4) showed a diminished response to the glucose load. No insulin delay was noted, but insulin output was lower than that seen in nonischemic transplants. The serum amylase response (Figure 5) of these glands with one hour ischemia and subjected to the trauma of transplantation was similar to that previously reported [5]. The post-transplant rise in serum amylase was profound and sustained. This response curve was much like that seen in pancreatic duct ligation in nontransplanted glands [6]. Amylase levels decreased coincidental with the acinar and parenchymal destruction of rejection. Group 11. Twelve dogs received a pancreas exposed to two hours of ischemia. Eight of the dogs: in this group were hyperglycemic on the first day after transplantation. Serum glucose values continued to increase until death. Seven of the deaths in this group were associated with respiratory infection, sepsis, or pulmonary embolism. Although one transplant was a technical failure, the remaining four preserved normoglycemia until death. Three of these animals died of respiratory infection on day five, and one died during rejection on day fifteen. Thus, only four of twelve transplants functioned well despite two hours of normothermic ischemia. Plasma insulin values in animals receiving a pancreas subj ected to two hours of ischemia were similar to those of group I. The characteristic pattern was of initial washout of gland insulin followed by decreasing values until death of the animal or rejection. (Table II.) Lack of prolonged recipient survival precluded glucose tolerance testing. Group III. Five animals received a pancreas which was ischemic for three hours or longer. One of these glands exhibited normal function and appeared normal on histologic examination when it was removed on day three. None of the other glands in this group showed satisfactory function although a variable amount of islet activity was present for three days in each. Comments
Experience from a number of laboratories has shown that the pancreas is a hardy gland which resists well the trauma and ischemia of conventional transplantation. Ischemia time necessitated by excision of the gland in the donor and vascular anastomosis in the recipient usually varies from ten to thirty minutes. Normal function is to be expected after this amount of normothermic ischemia The American Journal of Surgery
Pancreatic Function after Normothermic Ischemia 360 330 300 270 240 210 a! 180 ~ 150 .. 120
a~
90 60 30
60 55 50 45 40
,, I
I I I
INSULIN
,
GLUCOSE
I
I
35 Insuton 30 pU/ml 25 20 15 10
5 NOIlIlAL INSULIN RANGE
tl2345678910
Time In Days Figure 3. Plasma insulin values rose dramatically after transplantation of a gland sUbjected to one hour of ischemia. Hypoglycemia was not proportionate, however. TRANSPLANT
os'!
r ..
~ <;
220 200 180 160 140 120 100
120 100 00 80 70 60 Insulin 50 }lUI ml
80 60
40 30
40 20
20 10 oL - ; " - - -.........---.,;+----,.---,"--' 0 o 30 60 90 120
-----------, INSULIN
•
hill/itt I.~ GI._
Time in Minutes
Figure 4. The glucose tolerance test results are represented graphically. showing a diminished but adequate response by the pancreas ischemic for one hour.
6000 5600 5200 4800 4400 4000 ~ 3600 ~ 3200 2800 12400 .. 2000
j
1600 1200 800 400
o iii iii j f i i ~ TRAlISItUNT
Time ,n Day.
Figure 5. The high amylase values obtained after transplantation of a pancreas ischemic for one hour were indicative of persIsting acinar function until early rejection supervened.
even though perfusion, cooling, and other manipulation is not practiced. Similarly, after one hour of normothermic ischemia, the transplanted pancreas with duct ligated is able to maintain normoglycemia in the dog with no immune suppression until rejection occurs. Although glucose tolerance testing shows that the gland is able to respond to a glucose load, the ischemic and transplanted gland does not function normally. Its response to glucose challenge is sluggish and diminished as compared Volume 120. December 1970
to the normal. This is a logical response if one con-. siders the degree of ischemia which is produced. It is interesting to speculate whether or not endocrine function would improve after such an ischemic insult. There is no suggestion in this study that such, improvement occurs in the nonimmune modified animals but of course the ultimate answer awaits effective long-term control of rejection. In all three of the ischemia groups, an abnormally high level of plasma insulin was found after transplantation, a phenomenon which remains unexplained. However, the observation is consistent with the values found by a number of other inves-' tigators [7-9]. It has been thought in the past that post-transplant hyperinsulinemia was caused by bypass of hepatic insulinase by the heterotopic gland. However, the work of Starzl et al [10,11] and of Waddell and Sussman [12] shows that elevated plasma insulin is not caused by pancreatic blood reaching the systemic circulation rather than the portal circulation. More likely, the phenomenon of hyperinsulinemia is the result of islet damage from ischemia during the transplantation. This manifests itself as insulin washout immediately after revascularization of the gland in the recipient. The effects of transplantation ischemia seem to be persistent for some days after transplantation. They are similar to those of the in vivo ischemia studies previously reported. from this laboratory [2]. Later, the ischemia of the rejection process may contribute additional insulin release just prior to irreversible islet cell damage and ultimate hypoinsulinemia. Animals receiving pancreatic transplants under cover of immunosuppressive drugs show a prolonged period of plasma hyperinsulinemia [7,8]. -This may be caused by a smoldering rejection process. It is possible that the abnormally high level of insulin released by the islet cells would be of considerable duration if chronic rejection persisted. The paradoxical phenomenon of ischemia-induced insulin release can be explained. In the normal pancreatic beta cell, proinsulin is converted to insulin in the Golgi complex or in a stage intermediate between the endoplasmic reticulum and the Golgi, Insulin is stored in active form in the beta cell granules which are released by the simple process of emiocytosis. The beta cells are stimulated by hyperglycemia, after which the granules move to the surface of the cell where the membranous sacs enclosing the granules fuse to the plasma membrane. Rupture of this common wall causes release of the granule into the extracellular space where it undergoes immediate dissolution. Ischemia may act upon the plasma membrane of beta cells causing increased permeability to intra695
Cerra et al
cellular granules and their content of active insulin. The ischemia-damaged cell then may remain viable with a persistently permeable cell wall. If so, the beta cell would act in a fashion similar to intestinal mucosal cells which release potassium ion in response to ischemia and demonstrate increased cellular permeability after such trauma. Summary
Thirty-four cadaver pancreatic transplants were performed utilizing controlled ischemia times of one, two, and three or more hours. Although occasional function followed prolonged ischemia, normothermic ischemia tolerance of the pancreas appears to be about one hour. A paradoxical phenomenon of insulin washout was observed in all instances of revascularization after ischemia. Such insulin washout was not proportionate to duration of ischemia. References 1. Lillehei RC, et al: Pancreatico-duodenal allotransplanta_ tion. Ann Surg 172: 405, 1970. 2. Binder PS, Heiskell CA, Adams JR, Cerra FB, Eilert JB, Bergan JJ: Pancreatic function following normother-
696
3.
4. 5. 6. 7. 8. 9. 10.
11.
12.
mic ischemia. I. In vivo ischemia. Amer J Surg 120: 687,1970. Bergan JJ, Teixeira ED, Conn J Jr, Haid SP: Ex vivo pancreas perfusion. Organ Perfusion and Preservation (Norman, JC, ed). New York, Appleton-Century-Crofts, 1968. Bergan JJ, Hoehn JG, Porter N, Dry L: Total pancreatic allografts in pancreatectomized dogs. Arch Surg 90: 521, 1965. Teixeira ED, Bergan JJ: Auxiliary pancreas allografting. Arch Surg 95: 65, 1967. Ivy AC: Certain aspects of the applied physiology of external pancreatic secretion. Amer J Digest 3: 677, 1936. Ota K, Mori S, Inou T, Kanazawa Y, Kuzuya T: Endocrine function of the pancreatic allograft. Endocrinology 82: 731, 1968. Huguet C, Daloze P, Orcel L, Sussman KE: Endocrine function of pancreatic homotransplants in dogs. Arch Surg 98: 375, 1969. Teixeira ED, Sharkey E, Colwell J, Bergan JJ: Insulin and glucose levels following pancreas allografting. Surg Forum 17: 205,1966. Starzl TE, Scanlan WA, Yanof HM, Thornton FH, Wendel RM, Stearn B, Lazarus RE, McAllister W, Shoemaker WC: A comparison of hypoglycemic effect of insulin with systemic venous and portal venous administration. J Surg Res 3: 293, 1963. Starzl TE, Marchioro TL, Sexton AW, Illingworth B, Wad· dell WR, Faris TO, Herrmann TJ: The effect of portacaval transposition on carbohydrate metabolism: Experimental and clinical Observations. Surgery 57: 687, 1965. Waddell WR, Sussman KE: Plasma insulin after diversion of portal and pancreatic venous blood to vena cava. J Appl Physiol 22: 808, 1967.
The American Journal of Surgery