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Insights from a Successful Case of Intrahepatic Islet Transplantation into a Type 1 Diabetic Patient

Cattedra di Clinica Medica, Università Vita-Salute, Ospedale San Raffaele (A.M.D., P.M., L.F., G.P.); Departments of Pathology (F.S., M.F.) and Surgery (C.S., F.B., V.D.C.), Istituto Scientifico San Raffaele; and University of Milan (A.S.), 20132 Milan, Italy

Address all correspondence and requests for reprints to: Dr. Alberto M. Davalli, Cattedra di Clinica Medica, Università Vita-Salute, Hospital San Raffaele, Via Olgettina 60, 20132 Milan, Italy. E-mail: alberto.davalli{at}hsr.it

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We report a case of long-term (>4 yr) successful intrahepatic islet transplantation into a type 1 diabetic patient chronically immunosuppressed for a prior kidney graft. The exogenous insulin requirement decreased progressively after transplantation, and insulin treatment was withdrawn at 6 months. Glycosylated hemoglobin levels were in the normal range at 1 and 2 yr (5.3%) and increased slightly above the upper normal limit at 3 and 4 yr (6.3% and 6.4%). Fasting C peptide levels remained stable during the entire follow-up, but the proinsulin to insulin ratios increased dramatically at yr 3. Glycemic levels after an oral glucose tolerance test showed a diabetic profile at 1 yr, a normal profile at 2 yr, and an impaired glucose tolerance profile at 3 yr. Intravenous glucose tolerance test-induced first phase insulin release, present at 1 and 2 yr, disappeared at 3 yr. Diabetes-related autoantibodies (islet cell antibodies, glutamic acid decarboxylase antibodies, and tyrosine phosphatase-like protein antibodies) were undetectable before transplantation and remained so during the entire follow-up. The patient died of myocardial infarction 50 months after transplantation while she was still in good metabolic control (glycosylated hemoglobin, <6.8%) in the absence of exogenous insulin administration. The autoptic liver showed well granulated islets, richly vascularized and without evidence of lympho-mononuclear cell infiltration. The morphometrically extrapolated intrahepatic ß-cell mass was 99.9 mg. In conclusion, this successful islet graft showed a bell-shaped clinical effect, maximal at 2 yr after transplantation, followed by a slow progressive decline. The absence of allo- and autoreactivities against the transplanted islets points to a nonimmune-mediated ß-cell loss as the cause of graft functional deterioration.

	Introduction

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ALLOGENEIC ISLET transplantation can restore insulin production in C peptide-negative patients with type 1 diabetes mellitus (1, 2, 3, 4). A detailed analysis of the 200 diabetic patients transplanted with adult islets between 1990 and 1997 is available at the International Islet Transplantation Registry (5). Usually, islets are transplanted into the liver of long-term diabetic patients requiring immunosuppression for a prior or simultaneous kidney graft performed for end-stage diabetic nephropathy. Unfortunately, complete insulin independence is achieved in only a minority of these patients and often lasts for only a few months (5). Nevertheless, cases of long-term islet graft function have been reported even if small doses of exogenous insulin are generally required to maintain near-normal blood glucose and glycosylated hemoglobin (HbA_1c) levels (6). Long-term complete insulin independence has been also reported (7, 8), with 70 months being the longest period of insulin independence reported to date (5). Insulin independence for more than 3 yr has been obtained in a nondiabetic patient who received islet transplantation after pancreatectomy and liver replacement for diffuse abdominal cancer (9).

We report here the case of a type 1 diabetic patient who achieved long-term (>4 yr) insulin independence after islet transplantation. Graft metabolic efficiency and insulin secretion were studied during the entire posttransplantation follow-up period and showed a bell-shaped pattern of islet function. The patient died of myocardial infarction 50 months after transplantation while she was still without exogenous insulin. The intrahepatic ß-cell mass in the autoptic liver, calculated by morphometric analysis, was reduced to 15% of normal values, suggesting a progressive decrease in the transplanted ß-cell mass.

	Subjects and Methods

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Patient

The islet graft recipient was a 43-yr-old female with a diagnosis of type 1 diabetes from the age of 6 yr. At the age of 38 yr she started hemodialysis for end-stage diabetic nephropathy. She was also affected by diabetic retinopathy and neuropathy, coronary artery disease, and peripheral vascular disease. At the age of 41 yr she underwent simultaneous kidney and pancreas transplantations followed 6 days later by pancreatectomy because of organ thrombosis. The grafted kidney functioned immediately after transplantation, and its function was preserved for the entire patient’s follow-up. Chronic immunosuppressive therapy included azathioprine (100 mg/day), cyclosporin A (150 mg/day), and prednisone (10 mg/day). At the time of islet transplantation, the patient weighed 53 kg and required 50 IU insulin/day. The islet transplantation was approved by the ethics committee of Istituto Scientifico San Raffaele.

Islet transplantation

Islets were isolated using the automated method described by Ricordi (10) from two pancreases of cadaveric multiorgan donors obtained through the organ allocation network North Italian Transplant. After overnight culture, the islets were pooled, and a final preparation of 612,500 islet equivalents (number of islets with an average diameter of 150 µm) was infused percutaneously directly into the recipient’s portal vein as previously described (3). Antirejection induction therapy consisted of methylprednisolone (500 mg, iv, immediately before islet infusion) and a 7-day course of 125 mg/day antithymocyte globulin (Thymoglobulin, Merieux, Lyon, France). Chronic immunosuppression established for the prior kidney graft was continued, except for steroids, which were tapered to 2.5 mg/day in the first 6 months after transplantation. During the first 10 days after transplantation, tight metabolic control was maintained by continuous iv insulin infusion to keep blood glucose levels below 7.0 mmol/L. The patient was then discharged from the hospital and treated with intensive sc therapy until insulin withdrawal 6 months after transplantation.

Posttransplantation follow-up

After transplantation, blood glucose, serum C peptide [RIA (Diagnostic Products, Los Angeles, CA) with a reported cross-reactivity with proinsulin of about 25%] and HbA_1c levels were measured at least every 3 months. Fasting serum insulin [IMX system (Abbott Laboratories, Tokyo, Japan) that recognizes only mature insulin] and proinsulin [enzyme-linked immunosorbent assay (DAKO Corp., Ely, UK) that recognizes only proinsulin and does not cross-react with mature insulin and other intermediate forms] levels as well as C peptide, insulin, and glycemic responses to an oral glucose tolerance test (OGTT; 75 g) were performed yearly. Glycemic, C peptide, insulin, and proinsulin responses to iv glucose tolerance tests (IVGTT; 0.5 g/kg BW) were also performed yearly. IVGTT-induced first phase insulin release was calculated by summing the insulin values detected 1 and 3 min after glucose infusion; the insulin value at 30 min was considered representative of the second phase of secretion. Antibodies to islet cells (ICA), glutamic acid decarboxylase (GAD₆₅), and tyrosine phosphatase-like protein (IA-2) were measured before and yearly after transplantation as previously described (11).

Histology

The patient died 50 months after transplantation, and the autopsy confirmed myocardial infarction as the cause of death. The autoptic liver was weighed and cut in 1-cm-thick slices that were then fixed in 10% buffered formalin. Samples of the patient’s pancreas were also collected and fixed. Twenty random coronal and transversal liver samples (average size, 1 x 2 x 0.5 cm), collected from five different slices, were embedded in paraffin. From each liver sample, three to five series of 5-µm-thick sections were stained with hematoxylin and eosin and by immunohistochemical methods. Islet ß-, -, -, and pancreatic polypeptide cells were identified by antibodies against insulin (DAKO Corp., Carpinteria, CA), glucagon (DAKO Corp.), somatostatin (Bio-Optica, Milan, Italy), and pancreatic polypeptide (Medical System, Genova, Italy). Immunohistochemistry for islet hormones and chromogranin (Roche, Mannheim, Germany) was also performed on pancreas sections.

Morphometric analysis

The number and dimension of liver samples were considerate adequate to estimate the relative volume of intrahepatic islets using a stereological morphometric approach (12, 13). The sum of the areas of a representative hematoxylin- and eosin-stained section, from each series of sections of the 20 liver samples, was calculated and expressed as relative liver area (L_RA). The sum of the areas of any single islet found within the same liver sections, measured using a computerized image analysis system (Quinn 2, Leica Corp., Rockleigh, NJ) connected to the microscope, was calculated and expressed as relative islet area (I_RA). Relative islet ß- and -cell areas were measured similarly on seriate sections stained for insulin and glucagon, respectively, and were expressed as a percentage of the I_RA. Extrapolation of graft ß- and -cell relative volumes and masses were then obtained by assuming the liver and the islets were spheres of the same specific weight. Then liver and islet volumes (L_RV and I_RV) were calculated using the following formulas: L_RV = L_RA x r₁ x ⁴/₃ and I_RV = I_RA x r₂ x ⁴/₃ (where r₁ and r₂ are radii of the circles of L_RA and I_RA areas, respectively). Extrapolated total islet graft mass (I_GM) was then obtained by multiplying the liver weight for the I_RV/L_RV ratio and was expressed in milligrams. Finally, extrapolated ß- and -cell masses (ß-cell_GM and -cell_GM) were obtained by multiplying I_GM for relative ß- and -cell areas, respectively.

	Results

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Islet graft function

The function of the graft during the 4-yr follow up is summarized in Table 1. The insulin requirement progressively fell during the first months after transplantation, and insulin administration was completely withdrawn at 6 months. Excluding the 6 month value, HbA_1c levels remained always under 7% and at 1 and 2 yr were in the normal range of our laboratory (4.8–6%). According to the recent American Diabetes Association clinical practice recommendation guidelines (14), fasting blood glucose levels were in the normal range at 6 months and 2 yr and were in the impaired fasting glucose range at 1, 3, and 4 yr. Postprandial glucose levels were in the diabetic range at 6 months and 1 and 4 yr and were in the normal range at 2 and 3 yr. Fasting C peptide levels, undetectable before transplantation, rose to 1.58 nmol/L at 6 months and stabilized thereafter in the 0.60–0.80 nmol/L range. The IVGTT-induced first phase of insulin release was present at 1 and 2 yr, but disappeared at 3 yr. The second phase insulin release was also dramatically reduced at 3 yr. Fasting- and IVGTT-stimulated proinsulin secretion, low at 2 yr, was higher at 1 and 3 yr (Table 2). Proinsulin to insulin ratios, in the normal range at 2 yr, increased dramatically at 3 yr, when proinsulin was indeed the major secretory product released by the islet graft in response to iv glucose (Table 2). Blood glucose levels during OGTTs showed a diabetic profile at 1 yr, a normal glucose tolerance profile at 2 yr, and a glucose intolerance profile at 3 yr (Fig. 1, top). Dynamic insulin and C peptide releases in response to oral glucose were similar at all time periods, but the incremental increases were higher at 2 yr (Fig. 1, middle and bottom).

View larger version (16K): [in this window] [in a new window]   Figure 1. Blood glucose, insulin, and C peptide levels in response to OGTTs performed 1, 2, and 3 yr after transplantation. Glucose tolerance was in the diabetic range at 1 yr, in the normal range at 2 yr, and in the impaired glucose tolerance range at 3 yr. OGTT-induced insulin and C peptide releases showed similar kinetics at all time points, with the highest incremental responses (from 0–120 min) detected at 2 yr.

Histology and extrapolation of islet graft ß- and -cell masses in the autoptic liver

Liver histology showed the presence of well preserved islets localized in the portal spaces, richly vascularized and without evidence of lympho-mononuclear cellular infiltration (Fig. 2, top). Immunocytochemistry showed well granulated ß- and -cells (Fig. 2, middle and bottom). Insulin- and glucagon-positive cells were not homogeneously represented in the different islets, as shown in Fig. 3. Some islets (Fig. 3, a and b) were indeed particularly rich in ß-cells, whereas some others were rather deprived (Fig. 3, c and d). Somatostatin- and pancreatic polypeptide-positive cells were never detected (not shown). The complete morphometric analysis of the liver specimens for the extrapolation of islet graft ß- and -cell masses is reported in Table 3.

View larger version (83K): [in this window] [in a new window]   Figure 2. Histological analyses of a representative intrahepatic islet stained for hematoxylin and eosin (top), insulin (middle), and glucagon (bottom). Islets, localized in the portal spaces, did not show evidence of lympho-mononuclear cellular infiltration. Insulin- and glucagon-positive cells were easily detected, whereas somatostatin- and pancreatic polypeptide-secreting cells were never observed. Original magnification, x20.

View larger version (73K): [in this window] [in a new window]   Figure 3. Histological analyses of two intrahepatic islets stained for insulin (a and c) and glucagon (b and d). Note that the relative volume of insulin- and glucagon-positive cells is dramatically different in the two islets; the islet of a and b is particularly rich in ß-cells, which, conversely, are relatively scarce in the islet shown in c and d. Original magnification, x20.

View this table: [in this window] [in a new window]   Table 3. Relative ß- and -cell areas of the islets detected in random liver samples and extrapolation of ß- and -cell masses

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Islet transplantation induced long-term independence from exogenous insulin administration in this type 1 diabetic patient. However, despite the maintenance of near-normal HbA_1c levels through the entire posttransplantation follow-up, grafted islets showed a bell-shaped metabolic effectiveness and insulin secretory activity. Maximal graft function was achieved 2 yr after transplantation when 1) HbA_1c and glycemic levels were in the normal range; 2) IVGTT induced a clear first phase of insulin release; 3) OGTT showed a normal glucose tolerance profile; and 4) proinsulin to insulin ratios were in the normal range. Thus, about 18 months of good metabolic control were required to completely restore normal glucose homeostasis and insulin secretion by transplanted islets. The recovery from the immediate loss of islet tissue occurring after transplantation (15) and the time required to achieve graft revascularization cannot explain this time lag. Indeed, no more than 2 weeks are required for complete revascularization (16). Moreover, the low replicative potential of adult human ß-cells excludes their postimplantation growth as the cause of the improvement in function of the graft during the first 2 yr. Rather, the higher performance of the graft 2 yr after transplantation might reflect a qualitative improvement in ß-cell function. Perhaps, in view of the exquisite susceptibility of human pancreatic ß-cells to glucotoxicity (17), more than 1 yr of near-normoglycemia is required for restoration of physiological glucose sensing and insulin gene transcription by transplanted ß-cells.

Three years after transplantation, despite near-normal HbA_1c and glycemic levels, first phase insulin release disappeared, and OGTT showed an abnormal glucose tolerance profile. Moreover, 1 yr later (yr 4), HbA_1c levels were still under 7%, but postprandial glycemia was in the diabetic range. Baseline C peptide levels remained in the same range during the entire postimplantation follow-up, suggesting that C peptide is not an adequate measurement of islet graft function. In contrast, simultaneous assessments of insulin and proinsulin levels and calculation of the proinsulin to insulin ratio appeared to be more informative in this regard. Proinsulin to insulin ratios were in the normal range at 2 yr, but increased dramatically at 3 yr together with the appearance of other signs indicative of islet graft dysfunction. Increased proinsulin to insulin ratios have been shown in hemipancreatectomized patients (18) and suggest that in the presence of a reduced ß-cell mass and insulin secretory reserve, islets may compensate by recruiting immature secretory granules.

Why would an islet graft that restored completely normal glucose homeostasis at 2 yr, therefore, in a situation where glucotoxicity cannot be blamed for subsequent ß-cell damage then exhibit a progressive functional decline? The delayed impairment of islet graft function strongly suggests that a reduction of the transplanted ß-cell mass must have continuously occurred after transplantation. The amount of ß-cells required for successful islet transplantation has been only partially defined, but it has been suggested that 50% of the endocrine pancreatic mass would be theoretically enough (19). At the time of the patient’s death, extrapolated graft ß-cell mass was about 100 mg, presumably considerably lower than the ß-cell mass of the 612,500 islet equivalents originally transplanted and than that of a normal pancreas. Considering that the average weight of a normal adult female pancreas is about 100 g, with islets accounting for 1% of the entire pancreas mass, and that ß-cells are about 70% of the entire islet population, the ß-cell mass of a normal pancreas can be approximated to about 700 mg. Thus, the patient’s ß-cell mass was reduced to 15% of normal, a value strikingly similar to the residual ß-cell mass in type 1 diabetic patients at diagnosis (20), when insulin secretion abnormalities similar to those observed in this patient at 3 yr are also present (21, 22).

Auto- and alloreactivities against transplanted islets cannot be blamed as causes of the progressive ß-cell loss in this patient, as indicated by the fact that ICA, GAD₆₅, and I-A2 autoantibodies remained negative for the entire follow-up and by the lack of histological evidence of islet rejection. It has been suggested that intrahepatic islets, being vascularized by a mixture of portal vein and hepatic artery blood, might suffer from inadequate oxygen supply. Thus, the site of implantation might have contributed to the reduction of the mass of the engrafted ß-cell cells. However, the improvement of graft function observed during the first 2 yr tends to minimize this possibility. An important cause of delayed ß-cell loss may be the diabetogenicity of the immunosuppressive drugs used in this patient. Cyclosporin A has a direct negative effect on human ß-cells (23), and steroids, by inducing insulin resistance, might increase the metabolic demand placed on transplanted ß-cells, leading to their functional exhaustion over time. It is hoped that the trial of islet allotransplantation in type 1 diabetic patients recently started in Edmonton, which is based on a steroid- and cyclosporin-free immunosuppressive regimen (24), will be instructive in this regard.

Proliferation and differentiation of ductal epithelium cells participate in the regeneration of new ß-cells after partial pancreatectomy and other insults (25). Islet grafts are generally deprived of duct cell tissue, which is separated by the islets during the purification step of the isolation procedure and discarded. Lack of duct cells might preclude the capability of the graft to counteract in vivo ß-cell loss via this pathway of ß-cell regeneration. The presence of stem cells in the ducts of the adult pancreas, which can be expanded in vitro and differentiated into functional ß-cells (26, 27), further support the importance of the ductal epithelium for homeostasis of the ß-cell mass.

Engrafted islets showed a relatively preserved -cell population, suggesting that -cells are more resistant than ß-cells to in vivo cytotoxicity. The progressive increase in the -/ß-cell ratio of transplanted human islets (28) might negatively influence their function by worsening the hyperglucagonemia already present in type 1 diabetic patients (29). Hyperglucagonemia, through an increase in hepatic glucose production, might represent an additional challenge for the ß-cells and participate in their long-term exhaustion and death.

In conclusion, the delayed functional decline in this overall successful islet graft, presumably due to a progressive decrease in its ß-cell mass, was apparently unrelated to glucotoxicity, recurrence of autoimmunity, and chronic rejection. The lack of long-term stability of engrafted pancreatic islets may be overcome at least in part by the utilization of nondiabetogenic immunosuppressive drugs and treatments capable of selectively inhibiting glucagon secretion. However, cotransplantation of duct cell tissue would probably be required to achieve definitive stabilization of the ß-cell mass of pancreatic islet grafts.

	Acknowledgments

 
We thank Dr. Luciano Adorini for the helpful comments and for critically reading the manuscript. We are indebted to Drs. Mara Casorati and Silvia Gregori for image analysis and art works; Drs. Simona Braghi and Emanuele Bosi for measurements of ICA, GAD₆₅, and IA-2 autoantibodies; and Dr. Lucilla Monti for insulin, proinsulin, and C peptide assays.

Received June 5, 2000.

Accepted July 7, 2000.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Davalli, A. M. Articles by Secchi, A. Search for Related Content PubMed PubMed Citation Articles by Davalli, A. M. Articles by Secchi, A.