Original Article
Effects of Hemipancreatectomy on Insulin Secretion and Glucose Tolerance in Healthy Humans
N Engl J Med 1990; 322:898-903March 29, 1990
- Abstract
- Abstract
Pancreatic tissue obtained by hemipancreatectomy from healthy living related donors has been transplanted into recipients with Type I diabetes mellitus. To determine the metabolic consequences of this procedure for the donors, we carried out oral glucose-tolerance testing and 24-hour monitoring of serum glucose levels and urinary C-peptide excretion as a measure of insulin secretion in 28 donors, both before and one year after hemipancreatectomy.
The mean fasting serum glucose level was significantly higher one year after the procedure (mean ±SD, 5.4±0.9 vs. 4.9±0.5 mmol per liter; P<0.003), as was the serum glucose value two hours after the administration of glucose (8.7±2.9 vs. 6.5±1.0 mmol per liter; P<0.001). The fasting serum insulin level was significantly lower one year after hemipancreatectomy (33.0±21.6 vs. 38.4±21.6 pmol per liter; P<0.05), as was the area under the insulin curves during the oral glucose-tolerance test (52,554±22,320 vs. 76,230±33,354 pmol per liter per minute; P<0.04). The mean 24-hour serum glucose—profile value was higher at one year, and the 24-hour urinary C-peptide excretion was lower in the 17 donors who underwent these studies.
Seven of the 28 donors had abnormal glucose tolerance one year after hemipancreatectomy; however, insulin secretion in these 7 donors was indistinguishable from that in the 21 donors who had normal glucose tolerance. All 28 donors had fasting serum glucose concentrations lower than 7.8 mmol per liter, and their mean 24-hour plasma glucose levels remained within the normal range.
We conclude that in healthy donors hemipancreatectomy results in a deterioration of insulin secretion and glucose tolerance, as measured one year later. Further study is required to ascertain whether the development of clinical diabetes mellitus is a risk inherent in hemipancreatectomy. (N Engl J Med 1990; 322:898–903.)
Article Activity
- Article
COMPLETE glycemic control is not possible in patients with diabetes mellitus who are treated with conventional therapeutic regimens. Consequently, the potential therapeutic effects of the transplantation of pancreatic islets, segments of pancreas, and the entire pancreas continue to attract attention. All reported instances of the transplantation of islets in humans have failed to result in adequate glycemic control.1 In contrast, the successful transplantation of segments of the pancreas or the entire pancreas results in the long-term normalization of circulating glucose levels.2 In the centers with the most extensive experience in such transplantation procedures, the one-year survival rates of functioning pancreatic grafts range from 50 to 80 percent, and the patient survival rates are approximately 95 percent.3 4 5 6
In 1977, the University of Minnesota initiated a program of transplanting allografts of approximately half the pancreas from HLA-matched, living related donors to patients with Type I diabetes mellitus. The use of pancreatic segments from living related donors for transplantation was based on the premise that such grafts would be rejected less often than other types of graft. The idea that hemipancreatectomy was a reasonable procedure to perform was supported by published information on animal and human research, which indicated that pancreatic resection of this magnitude would not lead to diabetes mellitus.7 8 9 However, the duration of the reported studies in animals was short as compared with human longevity, and the earlier human studies of this issue were compromised both by the preexistence of pancreatic disease and by the limited duration of follow-up. Except for two case reports10 no previous studies have addressed the issue of whether hemipancreatectomy in healthy humans results in abnormal insulin secretion, carbohydrate intolerance, or both. To ascertain the metabolic consequences of this procedure in healthy donors, we performed the following studies before and one year after hemipancreatectomy in 28 subjects: oral glucose-tolerance tests with measurement of serum insulin and glucose levels, 24-hour monitoring of serum glucose levels, and 24-hour measurement of urinary C-peptide excretion as an indicator of integrated 24-hour insulin secretion.
Methods
Selection of Donors
Our criteria for the selection of donors have been outlined in an earlier report.2 Any donor had to be an adult and at least 10 years older than the age at which diabetes developed in the transplant recipient. The interval between the onset of diabetes in the recipient and hemipancreatectomy in the donor had to have been more than 10 years. Finally, all donors had to have normal results on preoperative measurements of insulin secretion and glucose tolerance. Potential donors were included if they and the intended recipients were HLA-identical or were matched at the HLA-DR3 or DR4 locus, because Barbosa et al. have shown that if diabetes is going to develop in a sibling or other family member of a diabetic patient, it does so within 10 years of the onset of diabetes in the patient.11 Since this program began at the University of Minnesota, 64 persons have undergone hemipancreatectomy. We have attempted to maintain contact with all previous donors regularly by registered mail in order to follow up their general health status. Twenty-eight of the 64 donors returned for formal studies of insulin secretion and glucose tolerance approximately one year (8 to 15 months) after hemipancreatectomy. The other 36 donors were not studied at one year because they lived far from our institution or because they had been lost to follow-up. The study was approved by the University of Minnesota Committee for the Use of Human Subjects in Research, and informed consent was obtained from all donors.
Operative Procedure
The operative technique used for hemipancreatectomy has been described in detail elsewhere.12 Briefly, the splenic vessels were isolated and ligated at the hilum of the spleen, leaving intact the short gastric, gastroepiploic, and other accessory vessels as collateral blood supply to the splenic parenchyma. The tail and distal body of the pancreas were mobilized, and the organ was divided surgically at its narrowest portion, where it overlies the portal vein. The pancreatic duct was ligated and the cut pancreatic surface oversewn. The splenic artery was divided and ligated at its origin in the celiac axis, as was the splenic vein at its termination in the portal vein. The distal pancreas was then removed from the donor for use as a transplant, leaving the pancreatic head and proximal tail intact in the donor. The amount of pancreatic tissue removed (approximately 50 percent) was standardized only by the operative technique, and the tissue was neither weighed nor biopsied before transplantation into the recipient.
Metabolic Studies
Among the 28 donors studied approximately one year after hemipancreatectomy, all underwent preoperative and postoperative oral glucose-tolerance tests. Sixteen donors had complete 24-hour serum glucose profiles and urinary C-peptide measurements, 1 had only the former, and 1 had only the latter; the 11 other donors did not have either of these tests. The donors were studied as inpatients at the General Clinical Research Center at the University of Minnesota, where they remained for five days.
Pancreatic endocrine function was studied after the donors had followed diets containing at least 300 g of carbohydrate per day for two days. During the first day of the study, 14 blood samples were collected, at 7:45 a.m., 9 a.m., 10 a.m., 11:45 a.m., 1 p.m., 2 p.m., 4:45 p.m., 6 p.m., 7 p.m., 8:50 p.m., 10 p.m., midnight, 4 a.m., and 7:45 a.m., for determination of the 24-hour serum glucose profile. Meals were eaten at 8 a.m., noon, and 5 p.m. The mean fasting serum glucose—profile value was calculated as the mean of the two values obtained 24 hours apart at 7:45 a.m., and the mean 1-hour and 2-hour postprandial glucose values were calculated from the appropriate values measured after each meal during this 24-hour period.
During each period of study, two to four 24-hour urine collections were obtained, and the mean 24-hour urinary C-peptide excretion was determined as an indicator of integrated insulin secretion.13 , 14 These samples were collected on all the days of the study, including the day of oral glucose-tolerance testing.
Oral glucose-tolerance tests were performed on the morning of the second study day, according to the method of Fajans and Conn.15 The glucose dose was 1.75 g per kilogram of ideal body weight, ingested as 50 percent glucose in water over a five-minute period. Blood samples were obtained for determination of serum glucose and insulin levels while the patient was fasting (10 and 5 minutes before the glucose was administered) and 15, 30, 60, 90, 120, 150, 180, 240, and 300 minutes after the administration of the glucose load. The criteria of the National Diabetes Data Group16 were used to designate donors as having normal or abnormal (impaired or diabetic) results on the oral glucose-tolerance test (these criteria are outlined in Table 1Table 1
Diagnostic Criteria of the National Diabetes Data Group for Oral Glucose-Tolerance Testing.*). For the postoperative oral glucose-tolerance test, donors were scored according to the fasting and two-hour glucose measurements. On this basis the donors were placed in one of two groups; those in Group 1 (n = 21) had normal (or non-diagnostic) results, whereas those in Group 2 (n = 7) had impaired glucose tolerance or results indicating the presence of diabetes.Assay Methods and Statistical Analysis
Serum glucose was measured by standard techniques with use of the Beckman glucose-analyzer system and a glucose oxidase reagent. Serum insulin was measured by the method of Goetz et al.17 Urinary C-peptide excretion was measured with antiserum M1230 obtained from Novo Research Institute, Copenhagen, Denmark, and an assay method described by Heding.18
For data storage and analyses, we used the CLINFO software system and statistical package at the University of Minnesota General Clinical Research Center. The areas under the insulin and glucose curves were calculated by standard trapezoidal methods. The results are given as means ±SD, unless otherwise noted, in the text and tables and means ±SE in the figures. The differences between groups were analyzed by means of two-tailed statistics including Student's t-test and a Wilcoxon two-sample rank-sum or signed rank-sum test, with the level of significance set at P<0.05.
Results
Donors
The 28 donors were 20 women and 8 men, and their mean age was 34±11 years at the time of hemipancreatectomy. Eighteen donors were HLA-identical to the recipients (including 4 who were the recipients' identical twins), and 10 were HLA-mismatched. Before the procedure, all had normal fasting serum glucose concentrations, normal results on the oral glucose-tolerance test, and normal 24-hour serum glucose—profile values. Their mean weight was 75.2±16.1 kg at the time of the hemipancreatectomy and 71.8±14.0 kg at the time of the postoperative study (P<0.01). No donor had any symptoms suggestive of pancreatic exocrine insufficiency at follow-up. Formal studies of pancreatic exocrine function were performed in a minority of these donors, and as previously reported,19 none had any evidence of exocrine insufficiency on the basis of fecal fat excretion.
Results and Complications of Hemipancreatectomy
Three of the 28 donors had complications of the hemipancreatectomy. Two required reexploration; one had a splenectomy because of splenic vascular compromise, and the other had an accumulation of sterile intraabdominal fluid in the region of the pancreatic resection, which was successfully aspirated percutaneously. As of August 1989, all 28 donors were alive and well 21±41 months after hemipancreatectomy (range, 1 to 8 years).
Metabolic Studies
The donors' mean fasting serum glucose level was significantly higher one year after hemipancreatectomy than the preoperative value (5.4±0.9 vs. 4.9±0.5 mmol per liter [97±16 vs. 88±7 mg per deciliter]; P<0.003; Fig. 1Figure 1
Mean (±SE) Serum Glucose and Serum Insulin Levels, Measured before and One Year after Hemipancreatectomy, during Five-Hour Oral Glucose-Tolerance Tests in 28 Transplant Donors.). Similarly, the mean serum glucose level two hours after the oral administration of glucose was significantly higher after one year (8.7±2.9 vs. 6.5±1.0 mmol per liter [156±53 vs. 117±18 mg per deciliter]; P<0.001). The mean of the area under the individual glucose curves during the five-hour oral glucose-tolerance test was also significantly higher after the hemipancreatectomy (2,202±455 vs. 1,843±178 mmol per liter per minute; P<0.003). The mean postoperative fasting serum insulin level was significantly lower than the preoperative value (33.0±21.6 vs. 38.4±21.6 pmol per liter; P<0.05; Fig. 2Figure 2
Mean (±SE) Serum Glucose Levels (Panels A and B) and Serum Insulin Levels (Panels C and D), Measured before and One Year after Hemipancreatectomy, during Five-Hour Oral Glucose-Tolerance Tests in 21 Transplant Donors with Normal Glucose Tolerance at One Year (Group 1) and 7 Donors with Abnormal Glucose Tolerance at One Year (Group 2).). The mean of the area under the insulin curve during the five-hour oral glucose-tolerance test was also significantly lower postoperatively (52,554±22,320 vs. 76,230±33,354 pmol per liter per minute; P<0.04).All the donors had normal results on the preoperative glucose-tolerance test, but seven (Group 2) had impaired or diabetic levels of glucose tolerance (defined by the National Diabetes Data Group criteria) as indicated by the results of the postoperative oral glucose-tolerance test (Table 1; Fig. 2). Before hemipancreatectomy, both serum glucose and serum insulin values during oral glucose-tolerance testing were similar in Group 1 and Group 2 (Fig. 2A and 2C). One year later, the serum insulin values were similar in the two groups (Fig. 2D), but there was a marked difference in the glucose levels (Fig. 2B). Despite the elevated postoperative serum glucose levels in the seven donors in Group 2 (Fig. 2B), the serum insulin levels of these patients were similar on both occasions (Fig. 2C and 2D). The body weights and ages of the donors in Group 1 and Group 2 were similar. Of the seven donors who had abnormal results on the oral glucose-tolerance test at one year, three were HLA-identical and four were HLA-mismatched with the recipients of the transplants. Six of the seven had the haplotype HLA-DR3, DR4, or DR3,4, whereas 16 of the 21 who had no change in their results on the oral glucose-tolerance test had the HLA-DR3, DR4, or DR3,4 haplotype (P not significant). Of the 28 donors, 4 were identical twins of the recipients. Of these four donors, three maintained normal glucose tolerance.
Twenty-four-hour serum glucose profiles were determined postoperatively for 17 of the 28 donors (11 with normal oral-glucose tolerance and 6 with abnormal glucose tolerance). Most serum glucose values were higher postoperatively than preoperatively (Fig. 3Figure 3
Twenty-Four-Hour Serum Glucose Profiles (Mean ±SE) before and One Year after Hemipancreatectomy in 17 Donors.), but the mean postoperative 24-hour glucose profile did not exceed the range in 72 normal subjects. In the donor group as a whole, there were significant increases over the preoperative values in the mean 24-hour, fasting, and 1-hour and 2-hour postprandial glucose values during the glucose profile study (Table 2Table 2
Twenty-Four-Hour Serum Glucose—Profile Values for Mean 24-Hour, Fasting, and One- and Two-Hour Postprandial Glucose Concentrations, Measured before and One Year after Hemipancreatectomy, in 17 Transplant Donors.*). The mean one-hour and two-hour postprandial serum glucose values in the individual groups were not higher postoperatively, although the differences observed between the two groups before surgery persisted at one year.The mean 24-hour urinary C-peptide—excretion values measured before and one year after hemipancreatectomy in 17 donors were 19.0±3.1 and 30.8±3.5 nmol per 24 hours, respectively (P<0.001). In 12 donors in Group 1, the 24-hour urinary C-peptide excretion fell from a preoperative value of 32.9±4.3 nmol per 24 hours to a postoperative value of 19.3±3.9 nmol per 24 hours (P<0.001). In five donors in Group 2, the preoperative value was 23.9±5.6 nmol per 24 hours, and the postoperative value was 18.3±5.3 nmol per 24 hours (P not significant). The preoperative and postoperative urinary C-peptide—excretion values did not differ significantly between the two groups.
In eight donors (six in Group 1 and two in Group 2) who were followed from two to seven years after hemi-pancreatectomy, none had further increases in fasting serum glucose concentrations, and all had fasting glucose values less than or equal to 5.5 mmol per liter (100 mg per deciliter) at the most recent examination (Fig. 4Figure 4
Fasting and Two-Hour Serum Glucose Levels during Oral Glucose-Tolerance Tests in Eight Donors Followed up for More Than Two Years.). Seven of those donors had two-hour plasma glucose values lower than 8.8 mmol per liter (160 mg per deciliter) during their most recent oral glucose-tolerance test, and in one the value was 13.1 mmol per liter (236 mg per deciliter). Two donors who had two-hour plasma glucose values of 10.1 and 11.2 mmol per liter one and two years after hemipancreatectomy subsequently had values lower than 8.8 mmol per liter.Discussion
This study was designed to determine whether hemipancreatectomy in healthy donors results in abnormalities in insulin secretion and glucose tolerance one year after the operation. We found that the removal of the distal half of the pancreas was associated with a deterioration in insulin secretion and glucose tolerance in all 28 donors, as indicated by oral glucose-tolerance testing one year later. According to the criteria of the National Diabetes Data Group, seven donors (Group 2) had abnormal results on glucose-tolerance tests one year after hemipancreatectomy. Insulin secretion in these 7 donors was comparable to that in the 21 donors (Group 1) who had normal glucose tolerance, indicating inappropriately low levels of insulin secretion, and thus inadequate beta-cell function, in relation to the degree of hyperglycemia during the oral glucose-tolerance test in the Group 2 donors. A relative dysfunction of islet beta cells was also suggested by the observation that 24-hour urinary C-peptide excretion in the seven Group 2 donors was similar to that in the Group 1 donors, although this measurement may not be as accurate an indicator of insulin secretion as measurements of plasma C-peptide levels.14 The comparable levels of insulin secretion in both groups also suggest a role for insulin resistance in the deterioration of glucose tolerance in the Group 2 donors. It should be emphasized, however, that despite some decreases in insulin secretion, increases in serum glucose levels during the oral glucose-tolerance test, and a reduction in urinary C-peptide excretion, the fasting serum glucose levels, fasting serum insulin levels, and daily fluctuations in serum glucose levels during a 24-hour sampling period were all within the normal range in all the donors. The results from the eight donors who were followed for two to seven years after hemipancreatectomy do not indicate any further decline in glucose tolerance.
There have been two previous reports concerning the metabolic consequences of hemipancreatectomy in healthy humans.10 , 19 One described a preliminary study from our institution in which increases in fasting and two-hour serum glucose levels and decreases in serum insulin levels after oral glucose administration were observed up to two years after the operation.19 The other report described three elderly donors, in two of whom the serum insulin level was measured.20 These donors had elevated serum glucose concentrations and reduced insulin concentrations after the oral and intravenous administration of glucose. Other reports describing the effects of the removal of substantial segments of the pancreas on insulin and glucose levels in large numbers of humans20 , 21 involved only patients with preexisting pancreatic disease.
In contrast to the limited previous information in humans, the metabolic effects of the resection of various amounts of pancreatic tissue have been examined extensively in animals.7 8 9 , 22 23 24 25 26 27 28 Sun et al. studied the metabolic effects of removing various amounts of the pancreas (approximately 20 to 88 percent) in dogs and found no significant metabolic changes unless more than 50 percent of the pancreas was removed.7 After 64 percent pancreatectomy in dogs, Ward et al. found defective arginine-induced but normal glucose-induced insulin secretion six weeks after surgery.27 Leahy et al.28 reported that 60 percent pancreatectomy in young rats did not cause hyperglycemia by four to six weeks, but the superimposition of mild hyperglycemia by the addition of sucrose to the animals' drinking water was associated with reduced insulin secretion and decreased insulin stores. Bonner-Weir et al. reported that 90 percent pancreatectomy in young rats led to hyperglycemia and defective insulin responses to glucose, but not to arginine, when insulin secretion was expressed as a function of residual beta-cell mass.25 The authors of the last two of these studies suggested that exposure of the residual beta cells to higher-than-normal circulating glucose concentrations led to the defects in insulin secretion.
These reports have immediate relevance to the findings in our study of humans who have undergone the resection of approximately 50 percent of the pancreas. The studies of Sun et al.7 suggest that our donors could be on the threshold of the eventual development of clinical diabetes mellitus, whereas the findings in animals after more extensive pancreatectomy suggest that the avoidance of even mild hyperglycemia in the donors may be important in preventing clinical diabetes. When one compares the report of Bonner-Weir et al.25 with that of Ward et al.,27 it is not entirely clear whether the insulin secretory response to intravenous glucose or to intravenous arginine provides the more sensitive index of abnormal insulin secretion. Consequently, both of these secretagogues should be used in future testing of donors who have undergone hemipancreatectomy.
In conclusion, hemipancreatectomy in healthy donors results in a deterioration in insulin secretion and glucose tolerance one year after surgery. Seven of the 28 donors we studied had abnormal glucose tolerance at follow-up; the development of glucose intolerance seems to be related to inadequate glucose-induced insulin secretion. Nonetheless, despite hemipancreatectomy, no donor had fasting hyperglycemia, and all had normal fasting serum insulin concentrations and normal 24-hour serum glucose profiles. Furthermore, no further deterioration occurred in any of the eight donors restudied from one to six years later. Whether diabetes mellitus will eventually develop in patients who have undergone hemipancreatectomy is not yet clear and can be determined only by studying a cohort such as ours for an extended period.
Supported by grants (R0I DK39994 and M0I RR00400) from the National Institutes of Health.
Presented in part at the First International Congress on Pancreatic and Islet Transplantation, Stockholm, Sweden, March 27–29, 1988, and referred to in the proceedings of the symposium (Diabetes 1989; 38:Suppl 1:101–3).
We are indebted to the staff of the General Clinical Research Center of the University of Minnesota for their superb support of this study.
Source Information
From the Diabetes Center and Endocrine Division, Department of Medicine (D.M.K., F.C.G., R.P.R.), and the Department of Surgery (D.E.R.S., J.S.N.), University of Minnesota Hospital and Clinic, Minneapolis. Address reprint requests to Dr. Kendall at the Diabetes Center, Box 101 UMHC, University of Minnesota, Minneapolis, MN 55455.
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