Original Article
Preserved Insulin Secretion and Insulin Independence in Recipients of Islet Autografts
N Engl J Med 1992; 327:220-226July 23, 1992
- Abstract
- Abstract
Background.
Transplantation of pancreatic islets, rather than whole pancreas, has been introduced as a treatment for diabetes mellitus. We studied five patients ranging in age from 12 to 37 years who had severe chronic pancreatitis for which they underwent total pancreatectomy followed by isolation and hepatic transplantation of their own islets.
Methods.
All patients had remained insulin-independent for 1 to 7 1/2 years after transplantation. The numbers of islets transplanted ranged from 110,000 to 412,000. Islet function was assessed by measuring the plasma insulin responses to intravenous glucose and arginine and the plasma glucagon responses to hypoglycemia and arginine. In one patient, islet function was studied during catheterization of the hepatic vein, portal vein, and splenic artery and by analysis of a liver-biopsy specimen.
Results.
After transplantation, the mean (±SD) fasting plasma glucose concentration was 122±47 mg per deciliter (6.8±2.6 mmol per liter) and the hemoglobin A1c concentration was 6.0±0.8 percent in the five patients. The values were most abnormal — 214 mg per deciliter (11.9 mmol per liter) and 7.3 percent, respectively — in the patient who received only 110,000 islets. The acute plasma insulin responses to glucose and to arginine in the five patients were 23±13 and 26±10 μU per milliliter (168±94 and 184±70 pmol per liter), respectively, as compared with 58±6 and 37±8 μU per milliliter (416±44 and 267±61 pmol per liter) in the normal subjects. The peak plasma glucagon responses to insulin and arginine were 21±4 and 65±36 pg per milliliter, respectively, as compared with 125±28 and 156±99 pg per milliliter in the normal subjects. All five patients had plasma epinephrine but not pancreatic polypeptide responses to hypoglycemia. The results of the hepatic-vein catheterization in one patient indicated that the transplanted islets released insulin and glucagon in response to arginine. Immunoperoxidase staining of this patient's liver-biopsy specimen showed that the islets contained insulin, glucagon, and somatostatin but not pancreatic polypeptide.
Conclusions.
Intrahepatic transplantation of as few as 265,000 islets can result in the release of insulin and glucagon at appropriate times and in prolonged periods of insulin independence. (N Engl J Med 1992;327: 220–6.)
Article Activity
- Article
THE amelioration of diabetes mellitus by the transplantation of pancreatic islets in animals has generated enthusiasm for the use of this procedure in humans with diabetes mellitus. If successful, islet transplantation would have advantages over transplantation of the entire pancreas. The procedure is shorter and easier, and the use of islets alone avoids the problem of exocrine drainage presented by the pancreatic allograft. However, there are only a few reports of transient successful transplantation of cadaveric islets in humans,1 2 3 4 5 and information about the secretion of hormones by the islets after successful transplantation is scant. Do the various types of islet cells (alpha, beta, delta, and pancreatic polypeptide) survive isolation, purification, and retransplantation with equal success? How many transplanted islets are required for insulin independence? Do transplanted islets secrete insulin and glucagon in a normal fashion? What effect does denervation of the transplanted islet have on the secretion of pancreatic hormones?
To address these questions, we studied the secretion of hormones by islets in five patients who underwent total pancreatectomy for painful chronic pancreatitis followed by intrahepatic transplantation of their own islets. These patients provide the opportunity to study hormone secretion from successfully transplanted isolated islets in the absence of immunosuppressive drugs, thereby avoiding the potentially deleterious effects of agents such as cyclosporine6 7 8 9 and prednisone10 on islet function and glucose homeostasis.
Methods
Patients
We studied five patients with severe, painful chronic pancreatitis (due to small-duct disease in Patients 1, 2, 4, and 5 and pancreas divisum in Patient 3) who underwent total or more than 99 percent pancreatectomy followed by intrahepatic transplantation of their own islets. These patients were included in the report by Farney et al.11 of 24 such patients. Of the 24 patients, 7 of the 8 patients who received more than 265,000 islets were insulin-independent for more than one year, as compared with only 2 of the 16 patients who received fewer than 265,000 islets. The five patients we studied (identified as Patients 13, 19, 23, 24, and 26 in the earlier study) were among the nine patients who remained insulin-independent. We obtained informed consent from Patients 2, 3, 4, and 5 and from the parents of Patient 1. All studies were approved by the University of Minnesota Committee on the Use of Human Subjects in Research.
All five patients had normal fasting plasma glucose concentrations preoperatively (mean [±SD], 86±11 mg per deciliter [4.8±0.6 mmol per liter]) and no history of diabetes mellitus. Preoperatively, the patients required intravenous hyperalimentation and narcotic analgesia. After transplantation, all patients were treated with pancreatic enzymes and Patients 2, 3, and 4 were treated with narcotics. Islets were isolated from the tail of the pancreas immediately after pancreatectomy.11 While the patients were still in the operating room, and within three hours of pancreatectomy, the islet preparation was infused into the portal vein while portal pressure was monitored. In Patients 1, 2, and 3, the number of islets was counted and insulin content was measured in aliquots of the islet preparation. The islets appeared whole and intact. In Patients 4 and 5, the number of islets transplanted was estimated from the insulin content of aliquots of their islet preparations and the mean insulin content per islet in Patients 1, 2, and 3.
None of the patients were taking insulin at the time of testing, and no patient took immunosuppressive drugs at any time after surgery. At the most recent examination, two patients were well without pain, one was pregnant and had intermittent pain, and two continued to have intermittent pain. The postoperative plasma pancreatic isoamylase concentrations in Patients 1, 2, 3, and 4 were 3, 6, 2, and 4 IU per liter (normal range, 1 to 46), respectively; the levels were undetectable (<2) in Patient 5. To compare the metabolic responses in patients with islet autografts with those in patients who had pancreatic allografts and no native pancreatic tissue, two additional patients (Patients 6 and 7) were studied. Both had undergone total pancreatectomy for painful chronic pancreatitis, followed by the transplantation of whole cadaveric pancreas with systemic venous drainage, and both were receiving immunosuppressive therapy (prednisone, azathioprine, and cyclosporine).
Beta-Cell Function and Glucose Tolerance
Patients 1, 2, 4, and 5 had an oral glucose-tolerance test using 75 g of glucose, frequent measurements of plasma glucose concentrations, or both. We used National Diabetes Data Group12 criteria to evaluate glucose tolerance. For the 24-hour profile, 14 blood samples were collected during normal activity and meals. The plasma insulin and C-peptide responses to intravenous glucose (20 g) and the plasma insulin, C-peptide, and glucagon responses to intravenous arginine (5 g) were determined. The plasma insulin, C-peptide, and glucagon responses and rates of glucose disappearance (expressed as the percentage disappearing per minute) were calculated as previously described.13 , 14
Function of Alpha and Pancreatic Polypeptide Cells and Counterregulation of Glucose
The plasma glucose, glucagon, pancreatic polypeptide, and catecholamine responses to insulin-induced hypoglycemia were determined as previously described.14 The response of plasma pancreatic polypeptide to 454 g (1 lb) of lean ground beef (80 g of protein, 93 g of fat, and 0 g of carbohydrate) consumed within 20 minutes was determined as described by Glaser et al.15 The results were compared with those in 25 normal subjects13 , 14 (mean [±SD] age, 34±14 years; 11 men and 14 women; body-mass index, 23.0±3.0; body-mass index is the weight in kilograms divided by the square of the height in meters). In addition, the results in each patient (except for Patient 1) were compared with the results in a normal subject matched for age, sex, and body-mass index.
Catheterization Study and Analytic Methods
Simultaneous samples for measurements of plasma insulin and glucagon were obtained from Patient 2 after catheterization of the right hepatic vein, splenic artery, and peripheral vein 5 and 0 minutes before the injection of 5 g of arginine and 0.5, 1, 2, 3, and 5 minutes after the injection.
Hemoglobin A1c values and plasma glucose, insulin, C-peptide, glucagon, pancreatic polypeptide, and epinephrine concentrations were measured in all patients according to previously described methods.13 , 14 , 16 We used high-performance liquid chromatography of a pool of plasma samples in Patient 6 to document that a single species of glucagon was produced. Plasma pancreatic isoamylase activity was determined with an EPS kit (Boehringer Mannheim). All assays were run in duplicate. Interassay variability was less than 10 percent. Immunoperoxidase staining was performed as described by Hsu et al.17 Statistical comparisons were performed with Student's t-test.
Results
Patients' Characteristics
The preoperative and postoperative clinical characteristics of the five patients who received islet autografts are shown in Table 1Table 1
Clinical Characteristics of Five Patients Who Underwent Pancreatectomy and Transplantation of Islet Autografts.*. The mean (±SD) portal pressure was 7.4±1.8 cm of water before the islet injection, and it increased to 28.1±10.8 cm of water after the injection. The number of islets injected ranged from 110,000 to 412,000. The interval between the injection of islets and the studies of islet function ranged from 3 weeks to 7 1/2 years. At the time of the study, the mean fasting plasma concentrations of glucose, insulin, and glucagon were 122±47 mg per deciliter (6.8±2.6 mmol per liter), 12± 10-μU per milliliter (90±70 pmol per liter), and 80±36 pg per milliliter, respectively, in the five patients, as compared with 86±7 mg per deciliter (n = 25; 4.8±0.4 mmol per liter), 9±0.7 μU per milliliter (n = 19; 66±5 pmol per liter), and 113±46 pg per milliliter (n = 16), respectively, in the group of normal subjects as a whole or with 90±4 mg per deciliter (5.0±0.2 mmol per liter), 8±1 μU per milliliter (57±7 pmol per liter), and 118±14 pg per milliliter, respectively, in the four normal subjects matched with Patients 2, 3, 4, and 5 (Table 2Table 2
Hormonal Responses of the Five Recipients of Intrahepatic Islet Autografts, Unmatched Normal Subjects, and Four Matched Normal Subjects.*). The fasting plasma glucose concentration in Patient 1, who received the fewest islets, was 214 mg per deciliter (11.9 mmol per liter), and it ranged from 92 to 113 mg per deciliter (5.1 to 6.3 mmol per liter) in Patients 2, 3, 4, and 5 (Table 1).Beta-Cell Function and Glucose Tolerance
After islet-cell transplantation, the timing of the plasma insulin responses to both glucose and arginine was normal, but the magnitudes of the responses were less than normal (Fig. 1Figure 1
Plasma Insulin Response to the Intravenous Administration of Glucose (20 g) and Arginine (5 g) in Five Patients with Intrahepatic Islet Autografts.). The mean plasma C-peptide response of Patients 1, 2, 3, 4, and 5 to glucose was 1.18±0.72 ng per milliliter (0.39±0.24 nmol per liter), as compared with 3.20±1.12 ng per milliliter (1.06±0.37 nmol per liter) in 19 normal subjects, and the mean C-peptide response to arginine was 1.24±0.60 ng per milliliter (0.41±0.20 nmol per liter), as compared with 2.33±1.24 ng per milliliter (0.77±0.41 nmol per liter) in 11 normal subjects. The values in the four matched normal subjects were 2.99±1.51 and 1.48±0.51 ng per milliliter (0.99±0.50 and 0.49±0.17 nmol per liter), respectively. The rates of glucose disappearance (Table 1) exceeded the lower limit of normal (>1.00 percent per minute) in two patients and were nearly normal in two patients; in Patient 1 the rate was normal four months (1.01 percent per minute) postoperatively but was decreased at two years (0.67 percent per minute). The pretransplantation plasma insulin and C-peptide responses and glucose-disappearance rates were greater than the post-transplantation responses in the two patients (Patients 2 and 3) who were studied before and after transplantation.The results of the oral glucose-tolerance tests and 24-hour plasma glucose profiles are shown in Figure 2Figure 2
Results of the Oral Glucose-Tolerance Test and the 24-Hour Glucose Profile after the Transplantation of Islet Autografts.. Patients 4 and 5 had normal glucose-tolerance tests. The test was normal in Patient 2 nine months after transplantation but met the criteria for diabetes mellitus three months later. Similarly, in Patient 1 the result was normal 4 months after transplantation and met the criteria for diabetes mellitus 20 months later. Hemoglobin A1c concentrations were normal in four of the five patients who received islet autografts (Table 1). Patient 1, despite having an abnormal glucose-tolerance test and an elevated hemoglobin A1c value, was insulin-independent. However, he was treated with small daily doses of long-acting insulin because of occasional hyperglycemia.Function of Alpha and Pancreatic Polypeptide Cells and Counterregulation of Glucose
During insulin-induced hypoglycemia, Patients 1, 2, 3, 4, and 5 had nadir plasma glucose concentrations of less than 43 mg per deciliter (less than 2.4 mmol per liter), and the levels increased to 63±27 mg per deciliter (3.5±1.2 mmol per liter) within 60 minutes after insulin injection. All five patients had marked adrenergic symptoms typical of hypoglycemia. None had a plasma glucagon response to insulin-induced hypoglycemia, whereas all had definite although subnormal plasma glucagon responses to the administration of arginine (Fig. 3Figure 3
Plasma Glucagon Responses to the Intravenous Administration of Insulin and Arginine in Five Recipients of Islet Autografts.); Patients 2 and 3 both had substantial plasma glucagon responses to insulin-induced hypoglycemia and arginine before transplantation. The two patients (Patients 6 and 7) who had undergone pancreatectomy followed by transplantation of the entire pancreas had peak plasma glucagon responses to insulin of 432 and 276 pg per milliliter and peak plasma glucagon responses to arginine of 269 and 362 pg per milliliter.The peak plasma epinephrine response to hypoglycemia in Patients 1, 2, 3, 4, and 5 was 975±608 pg per milliliter (5320±3320 pmol per liter), as compared with 476±220 pg per milliliter (2600±1200 pmol per liter) in 10 normal subjects (P<0.05) and 596±295 pg per milliliter (3255±1611 pmol per liter) in the 4 matched normal subjects (P>0.05). None of the five patients had plasma pancreatic polypeptide responses to insulin-induced hypoglycemia or to the ingestion of a high-protein meal, although both Patients 2 and 3 had plasma pancreatic polypeptide responses to insulin-induced hypoglycemia before transplantation. The two patients (Patients 6 and 7) who underwent transplantation of the entire pancreas also had no pancreatic polypeptide responses to insulin-induced hypoglycemia, but in contrast to Patients 1, 2, 3, 4, and 5, they did have a response to the ingestion of a high-protein meal. They had peak plasma pancreatic polypeptide responses to insulin of less than 4 and 29 pg per milliliter (<1 and 7 pmol per liter) and to the meal of 815 and 105 pg per milliliter (195 and 25 pmol per liter). The peak plasma pancreatic polypeptide response to insulin-induced hypoglycemia in 16 normal subjects was 815±635 pg per milliliter (195±152 pmol per liter), and it was 1296±991 pg per milliliter (310±237 pmol per liter) in the 4 matched normal subjects.
Fractionation of plasma samples from Patient 6 after administration of insulin and arginine revealed a single peak of radioimmunoactivity corresponding to that of highly purified porcine glucagon.
Concentrations of Hepatic-Vein Insulin and Glucagon and Liver-Biopsy Findings
To verify that the insulin and glucagon measured in peripheral plasma were secreted from the transplanted islets rather than residual native islets, we measured the plasma insulin and glucagon responses to intravenous arginine during a splenectomy, just before the liver biopsy in Patient 2. The splenectomy was performed because of shortened red-cell survival and anemia. The portal venous pressure at the time of the splenectomy was 9 cm of water. After the injection of 5 g of arginine into an antecubital vein, the peak plasma insulin concentration in the hepatic vein was 79 μU per milliliter (570 pmol per liter) at 30 seconds, the peak concentration in the splenic artery was 31 μU per milliliter (224 pmol per liter) at 30 seconds, and the peak concentration in the portal vein was 29 μU per milliliter (211 pmol per liter) at 2 minutes (Fig. 4Figure 4
Plasma Insulin and Glucagon Responses to the Intravenous Administration of Arginine in Patient 2 Seven Months after Islet Transplantation, as Measured in the Hepatic Vein, Splenic Artery, and Portal Vein.). The peak plasma glucagon concentration was 415 pg per milliliter at 30 seconds in the hepatic vein, 190 pg per milliliter at 30 seconds in the splenic artery, and 144 pg per milliliter at 2 minutes in the portal vein. Study of the liver-biopsy specimen revealed islets within the liver parenchyma. The immunohistologic studies revealed positive staining for insulin, glucagon, and somatostatin within islets, but no staining for pancreatic polypeptide (Fig. 5Figure 5
Liver-Biopsy Specimen from Patient 2 Seven Months after Islet Transplantation, Demonstrating Intrahepatic Islets (Immunoperoxidase, ×60).). The alpha cells were normally oriented in the periphery, and the beta cells were in the center of the islets.Discussion
We found that recipients of as few as 265,000 autografted islets had normal fasting plasma glucose concentrations and normal hemoglobin A1c values for up to 7 1/2 years after transplantation. One patient who received 110,000 islets was insulin-independent for more than two years, although he had mild hyperglycemia. Two of the patients had normal glucose-tolerance tests, another two patients had normal 24-hour plasma glucose profiles, and all patients secreted insulin and C peptide in response to the intravenous administration of insulin and arginine.
In contrast to the normal timing of insulin secretion, there was little response of glucagon to insulin-induced hypoglycemia, although the recovery of glucose levels was adequate, presumably because the plasma epinephrine responses were normal or increased. All five patients with islet autografts had plasma glucagon responses to the intravenous administration of arginine, but the responses were subnormal, and no patient had a change in plasma pancreatic polypeptide levels in response to either hypoglycemia or food ingestion. In contrast, patients who had total pancreatectomy followed by transplantation of cadaveric pancreas had plasma glucagon responses to hypoglycemia and pancreatic polypeptide responses to the ingestion of a high-protein meal. However, the recipients of allografts ate 454 g (1 lb) of beef, whereas the autograft recipients were able to consume an average of only 227 g (0.5 lb). In one patient we documented the secretion of insulin and glucagon from the intrahepatic transplanted islets by simultaneously measuring plasma insulin and glucagon concentrations in the hepatic vein, portal vein, and splenic artery. Immunoperoxidase staining of a liver-biopsy specimen revealed the presence of insulin, glucagon, and somatostatin but not of pancreatic polypeptide in the transplanted islets.
Insulin independence has previously been demonstrated in patients after pancreatectomy and transplantation of intrahepatic islet autografts for chronic pancreatitis.18 19 20 However, in many of these patients the pancreatectomy was not complete, the duration of insulin independence was short-lived, and the ability of the islets to secrete hormones was not studied. The failure of this procedure has been attributed to technical problems with the isolation of islets from fibrotic pancreatic tissue, the presence of glucose intolerance before transplantation, and the development of elevated portal pressure, hypotension, and disseminated intravascular coagulation after islet infusion.19
A few patients with insulin-dependent diabetes have had a transient return of the ability to secrete C peptide after the transplantation of 500,000 to 1,130,000 islets obtained post mortem from several pancreata.2 , 3 , 5 In contrast to our patients, these patients were treated with immunosuppressive drugs, which are known to compromise beta-cell function and whose use has been associated with impaired synthesis and secretion of insulin, hyperglycemia, and insulin resistance.6 7 8 9 10 There is one report of a patient with insulin-dependent diabetes who, after receiving only 200,000 allogeneic islets, was able to maintain normal blood glucose levels without insulin therapy.1 This report generally supports the prediction of Weir et al.21 that the transplantation of at least 200,000 to 250,000 islets should ameliorate diabetes in humans.
There are several possible explanations for the different responses of plasma glucagon to hypoglycemia and to arginine. They include a lack of islet innervation or activation by various polypeptides, decreased alpha-cell mass, and a change in the level of alpha-cell secretion because of their hepatic location. The autonomic nervous system may contribute to the process of glucagon secretion in response to hypoglycemia.22 However, studies using parasympathetic or sympathetic blockade suggest that its contribution may not be essential to these responses23 24 25 and that denervated islets can secrete glucagon in response to both arginine and hypoglycemia.26 27 28 29 Moreover, the level of glucagon secreted in response to hypoglycemia is increased in patients with insulin-dependent diabetes after transplantation with a denervated cadaveric pancreas.14 Peptidergic activation of glucagon secretion has been demonstrated, but whether it has a role in the secretion of glucagon during hypoglycemia is unresolved.22 , 30 31 32 33 In any event, our patients had adequate levels of epinephrine. Their ability to recover from hypoglycemia despite having poor glucagon responses is strongly reminiscent of the nearly normal glucose responses as a result of epinephrine secretion in patients with other glucagon-deficient states.34 There was no response of plasma pancreatic polypeptide to insulin-induced hypoglycemia in the patients who had undergone islet transplantation after pancreatectomy or in those who had received pancreatic allografts, whereas there was no response of pancreatic polypeptide to a high-protein meal only in the patients who had received islet autografts. The differences in the responses to the meal between the two groups of patients cannot be explained by differences in innervation, because innervation was absent in all patients. Since the pancreatic tail contains few pancreatic polypeptide cells,35 it seems likely that the lack of plasma pancreatic polypeptide responses to a meal in the patients who had received islet autografts resulted from the transplantation of islets from the tail of the pancreas.
In conclusion, we have shown that intrahepatic islet-cell autografts in patients with chronic pancreatitis secrete insulin, C peptide, and glucagon appropriately. The demonstration that insulin independence can be maintained for a prolonged period by a relatively small number of islets supports the view that rejection, rather than insufficient numbers, of islets is most likely to be the greater barrier for successful islet allotransplantation.
Supported by grants (R01 DK 39994, M01 RR 00400, and 5T32 DK 07203) from the National Institutes of Health.
We are indebted to the nursing and laboratory staff of the University of Minnesota General Clinical Research Center for skilled patient care and excellent technical assistance, to Ms. Paula Rossin and Ms. Mersini Spiropoulos for assistance in the preparation of the manuscript, and to Fred S. Apple, Ph.D., Hennepin County Medical Center, for his contributions to the manuscript.
Source Information
From the Diabetes Center and the Division of Endocrinology and Metabolism, Departments of Medicine (K.L.P., D.M.K., R.P.R.), Surgery (D.E.R.S.), and Laboratory Medicine and Pathology (R.E.N.), University of Minnesota, Minneapolis, and the Department of Medicine, University of Michigan and the Veterans Affairs Medical Center, Ann Arbor (J.B.H.). Address reprint requests to Dr. Robertson at the Diabetes Center, Box 101 UMHC, University of Minnesota, Minneapolis, MN 55455.
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