Islet Transplantation in Seven Patients with Type 1 Diabetes Mellitus Using a Glucocorticoid-Free Immunosuppressive Regimen
27 Jul 2000-The New England Journal of Medicine (Massachusetts Medical Society)-Vol. 343, Iss: 4, pp 230-238
TL;DR: The observations in patients with type 1 diabetes indicate that islet transplantation can result in insulin independence with excellent metabolic control when glucocorticoid-free immunosuppression is combined with the infusion of an adequate islet mass.
Abstract: Background Registry data on patients with type 1 diabetes mellitus who undergo pancreatic islet transplantation indicate that only 8 percent are free of the need for insulin therapy at one year. Methods Seven consecutive patients with type 1 diabetes and a history of severe hypoglycemia and metabolic instability underwent islet transplantation in conjunction with a glucocorticoid-free immunosuppressive regimen consisting of sirolimus, tacrolimus, and daclizumab. Islets were isolated by ductal perfusion with cold, purified collagenase, digested and purified in xenoprotein-free medium, and transplanted immediately by means of a percutaneous transhepatic portal embolization. Results All seven patients quickly attained sustained insulin independence after transplantation of a mean (±SD) islet mass of 11,547±1604 islet equivalents per kilogram of body weight (median follow-up, 11.9 months; range, 4.4 to 14.9). All recipients required islets from two donor pancreases, and one required a third transplant from tw...
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TL;DR: Current progress in epidemiology, pathology, diagnosis, and treatment of type 1 diabetes, and prospects for an improved future for individuals with this disease are discussed.
1,881 citations
TL;DR: Islet transplantation with the use of the Edmonton protocol can successfully restore long-term endogenous insulin production and glycemic stability in subjects with type 1 diabetes mellitus and unstable control, but insulin independence is usually not sustainable.
Abstract: Background Islet transplantation offers the potential to improve glycemic control in a subgroup of patients with type 1 diabetes mellitus who are disabled by refractory hypoglycemia. We conducted an international, multicenter trial to explore the feasibility and reproducibility of islet transplantation with the use of a single common protocol (the Edmonton protocol). Methods We enrolled 36 subjects with type 1 diabetes mellitus, who underwent islet transplantation at nine international sites. Islets were prepared from pancreases of deceased donors and were transplanted within 2 hours after purification, without culture. The primary end point was defined as insulin independence with adequate glycemic control 1 year after the final transplantation. Results Of the 36 subjects, 16 (44%) met the primary end point, 10 (28%) had partial function, and 10 (28%) had complete graft loss 1 year after the final transplantation. A total of 21 subjects (58%) attained insulin independence with good glycemic control at any point throughout the trial. Of these subjects, 16 (76%) required insulin again at 2 years; 5 of the 16 subjects who reached the primary end point (31%) remained insulin-independent at 2 years. Conclusions Islet transplantation with the use of the Edmonton protocol can successfully restore long-term endogenous insulin production and glycemic stability in subjects with type 1 diabetes mellitus and unstable control, but insulin independence is usually not sustainable. Persistent islet function even without insulin independence provides both protection from severe hypoglycemia and improved levels of glycated hemoglobin. (ClinicalTrials.gov number, NCT00014911.)
1,784 citations
TL;DR: The use of RAPA, instead of cyclosporine, may reduce the chance of recurrent or de novo cancer in high-risk transplant patients and show antiangiogenic activities linked to a decrease in production of vascular endothelial growth factor and to a markedly inhibited response ofascular endothelial cells to stimulation by VEGF.
Abstract: Conventional immunosuppressive drugs have been used effectively to prevent immunologic rejection in organ transplantation. Individuals taking these drugs are at risk, however, for the development and recurrence of cancer. In the present study we show that the new immunosuppressive drug rapamycin (RAPA) may reduce the risk of cancer development while simultaneously providing effective immunosuppression. Experimentally, RAPA inhibited metastatic tumor growth and angiogenesis in in vivo mouse models. In addition, normal immunosuppressive doses of RAPA effectively controlled the growth of established tumors. In contrast, the most widely recognized immunosuppressive drug, cyclosporine, promoted tumor growth. From a mechanistic perspective, RAPA showed antiangiogenic activities linked to a decrease in production of vascular endothelial growth factor (VEGF) and to a markedly inhibited response of vascular endothelial cells to stimulation by VEGF. Thus, the use of RAPA, instead of cyclosporine, may reduce the chance of recurrent or de novo cancer in high-risk transplant patients.
1,701 citations
Cites background from "Islet Transplantation in Seven Pati..."
...This activity, which effectively blocks IL-2 stimulation of lymphocyte division, is the basis for the recent successful clinical use of RAPA to prevent allograft rejection in organ transplantatio...
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TL;DR: This work generated cells expressing insulin and other pancreatic endocrine hormones from mouse ES cells that self-assemble to form three-dimensional clusters similar in topology to normal pancreatic islets where pancreatic cell types are in close association with neurons.
Abstract: Although the source of embryonic stem (ES) cells presents ethical concerns, their use may lead to many clinical benefits if differentiated cell types can be derived from them and used to assemble functional organs. In pancreas, insulin is produced and secreted by specialized structures, islets of Langerhans. Diabetes, which affects 16 million people in the United States, results from abnormal function of pancreatic islets. We have generated cells expressing insulin and other pancreatic endocrine hormones from mouse ES cells. The cells self-assemble to form three-dimensional clusters similar in topology to normal pancreatic islets where pancreatic cell types are in close association with neurons. Glucose triggers insulin release from these cell clusters by mechanisms similar to those employed in vivo. When injected into diabetic mice, the insulin-producing cells undergo rapid vascularization and maintain a clustered, islet-like organization.
1,634 citations
TL;DR: In conclusion, islet transplantation can relieve glucose instability and problems with hypoglycemia and point to the need for further progress in the availability of transplantable islets, improving islet engraftment, preserving islet function, and reducing toxic immunosuppression.
Abstract: Islet transplantation can restore endogenous beta-cell function to subjects with type 1 diabetes. Sixty-five patients received an islet transplant in Edmonton as of 1 November 2004. Their mean age was 42.9 +/- 1.2 years, their mean duration of diabetes was 27.1 +/- 1.3 years, and 57% were women. The main indication was problematic hypoglycemia. Forty-four patients completed the islet transplant as defined by insulin independence, and three further patients received >16,000 islet equivalents (IE)/kg but remained on insulin and are deemed complete. Those who became insulin independent received a total of 799,912 +/- 30,220 IE (11,910 +/- 469 IE/kg). Five subjects became insulin independent after one transplant. Fifty-two patients had two transplants, and 11 subjects had three transplants. In the completed patients, 5-year follow-up reveals that the majority ( approximately 80%) have C-peptide present post-islet transplant, but only a minority ( approximately 10%) maintain insulin independence. The median duration of insulin independence was 15 months (interquartile range 6.2-25.5). The HbA(1c) (A1C) level was well controlled in those off insulin (6.4% [6.1-6.7]) and in those back on insulin but C-peptide positive (6.7% [5.9-7.5]) and higher in those who lost all graft function (9.0% [6.7-9.3]) (P < 0.05). Those who resumed insulin therapy did not appear more insulin resistant compared with those off insulin and required half their pretransplant daily dose of insulin but had a lower increment of C-peptide to a standard meal challenge (0.44 +/- 0.06 vs. 0.76 +/- 0.06 nmol/l, P < 0.001). The Hypoglycemic score and lability index both improved significantly posttransplant. In the 128 procedures performed, bleeding occurred in 15 and branch portal vein thrombosis in 5 subjects. Complications of immunosuppressive therapy included mouth ulcers, diarrhea, anemia, and ovarian cysts. Of the 47 completed patients, 4 required retinal laser photocoagulation or vitrectomy and 5 patients with microalbuminuria developed macroproteinuria. The need for multiple antihypertensive medications increased from 6% pretransplant to 42% posttransplant, while the use of statin therapy increased from 23 to 83% posttransplant. There was no change in the neurothesiometer scores pre- versus posttransplant. In conclusion, islet transplantation can relieve glucose instability and problems with hypoglycemia. C-peptide secretion was maintained in the majority of subjects for up to 5 years, although most reverted to using some insulin. The results, though promising, still point to the need for further progress in the availability of transplantable islets, improving islet engraftment, preserving islet function, and reducing toxic immunosuppression.
1,620 citations
References
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TL;DR: It was deemed essential to develop an appropriate, uniform terminology and a functional, working classification of diabetes that reflects the current knowledge about the disease.
Abstract: the growth of knowledge regarding the etiology and pathogenesis of diabetes has led many individuals and groups in the diabetes community to express the need for a revision of the nomenclature, diagnostic criteria, and classification of diabetes. As a consequence, it was deemed essential to develop an appropriate, uniform terminology and a functional, working classification of diabetes that reflects the current knowledge about the disease. (1)
11,886 citations
TL;DR: Three cases illustrate that pentoxifylline, in conjunction with intensive therapy for diabetes, may be particularly useful in reducing significant proteinuria in patients with macroalbuminuria from diabetic nephropathy.
Abstract: tight glycemic control, in the treatment of patients with macroalbuminuria from diabetic nephropathy. In the first case, a 58-year-old woman with type 1 diabetes that was diagnosed when she was 17 years old was found to have 1,260 mg/day of protein in the urine. Her history was pertinent for diabetic retinopathy neuropathy, and for recurrent congestive heart failure. Medications included digoxin, furosemide, Cozaar, and aspirin, as well as NPH and regular insulin twice daily. The HbAlcwas 7.7% (4.1-6.1). The treatment regimen was changed to the insulin pump, and therapy with pentoxifylline (400 mg t.i.d.) was begun. Because of gastrointestinal side effects from the pentoxifylline, the dosage was reduced to 400 mg twice per day, which was tolerated. Three months later, the 24-h urine protein was 284 mg/day, and 6 months after that, 237 mg/day. The HbAlc fluctuated between 7.2 and 7.5% during that time. All other medications were continued as before. In the second case, a 74-year-old man with type 1 diabetes that was diagnosed when he was 42 years old had been noted at age 70 years to have 312 mg/day of protein in the urine. Therapy with 10 mg/day lisinopril was begun. After 18 months, a 24-h urine sample revealed 3,643 mg/day of protein. Therapy with pentoxifylline (400 mg t.i.d.) was begun. Also at that time, the insulin regimen was changed from three injections per day to use of the insulin pump. After 6 months, a 24-h urine sample revealed 1,836 mg of protein. When tested 6 months later, the urinary protein was 1,056 mg/day and after an additional 6 months, it was 490 mg/day Lisinopril therapy was continued during this time. HbAlc levels fluctuated between 7.2 and 8.3% (4.1-6.1) during this time, compared with values between 9.0 and 9.3% before introduction of the insulin pump. In the third case, an 84-year old female who had type 2 diabetes with diabetic retinopathy and peripheral neuropathy was found to have 3,967 mg/day of urinary protein. Her history was pertinent for hypertension and congestive heart failure, for which she was treated with captopril (25 mg t.i.d.) and furosemide (40 mg b.i.d.). Her diabetes was managed with Humulin N and Humulin R in the morning, Humulin R at supper, and Humulin N at bedtime. Pentoxifylline was begun for the proteinuria at a dosage of 400 mg t.i.d. After 4 months, the 24-h urinary protein had been reduced to 733 mg/day, and 1 year later, the urinary protein was 787 mg/day. During this time, HbAlc ranged between 5.8 and 6.5% (4.1-6.1). These cases illustrate that pentoxifylline, in conjunction with intensive therapy for diabetes, may be particularly useful in reducing significant proteinuria. All three patients maintained stable serum creatinine levels in the range of 1.0-1.5 mg/dl. Tight glycemic control was maintained in all patients, and in the second case, there was a significant improvement in HbAlc after insulin pump therapy was introduced. Two patients were taking concomitant ACEls, and the third was on an angiotensin-receptor blocker (ARB). ARBs have been shown in .an animal model to attenuate diabetic nephropathy (7). Further studies to elucidate the mechanism of improved macroalbuminuria by pentoxifylline in conjunction with tight glycemic control in the treatment of diabetic nephropathy should be considered. This treatment appears to be beneficial in forestalling the typically relentless downhill course of diabetic nephropathy.
1,830 citations
TL;DR: The persistently large value of MAGE despite therapy with multiple injections of short-acting insulin appears to be a characteristic of unstable diabetes.
Abstract: Three normal, three stable diabetic, and eight unstable diabetic subjects were investigated, with continuous automated blood glucose analysis for forty-eight-hour periods, during metabolic balance studies of six days9 duration under near normal conditions (fed and ambulatory) after the attainment of clinically optimal diabetic regulation. The studies on unstable diabetics were performed during constant dietary intake, with one or two daily injections of intermediate-acting insulin and then repeated with four daily injections of short-acting insulin. A characteristic of blood glucose behavior, the mean amplitude of glycemic excursion (MAGE), was measured. MAGE was small for normals (range, 22 to 60 mg./100 ml.), larger for stable diabetics (67 to 82 mg./100 ml.), and largest for unstable diabetics (119 to 200 mg./100 ml.). Associated with a significant decrease ( p = 0.004) in the mean diurnal glycemic level (from 146 to 244 mg,/100 ml. to 101 to 152 mg./100 ml.) achieved through the use of four daily doses of short-acting insulin there was a significant increase ( p = 0.006) in hypoglycemic episodes (from 0 to 4/48 hr. to 3 to 6/48 hr.) without significant change in MAGE. The persistently large value of MAGE despite therapy with multiple injections of short-acting insulin appears to be a characteristic of unstable diabetes.
1,060 citations
TL;DR: Sirolimus (rapamycin) is a potent immunosuppressant with a mechanism of action different from cyclosporine (CsA) or tacrolimus as discussed by the authors.
Abstract: Background. Sirolimus (rapamycin) is a potent immunosuppressant with a mechanism of action different from cyclosporine (CsA) or tacrolimus. Methods. In 11 European centers, first cadaveric renal allograft recipients were randomized to CsA (n=42) or sirolimus (n=41). Dosing of these agents was concentration-controlled and open-labeled. All patients received corticosteroids and azathioprine. Results. At 12 months, graft survival (98% sirolimus vs. 90% CsA), patient survival (100% vs. 98%), and incidence of biopsy-confirmed acute rejection (41% vs. 38%) were similar. Serum creatinine was lower with sirolimus, significantly (P<0.05) so at 3 and 4 months, and serum uric acid and magnesium were normal. Laboratory abnormalities reported significantly more often with sirolimus included hypertriglyceridemia (51% vs. 12%), hypercholesterolemia (44% vs. 14%), thrombocytopenia (37% vs. 0%), leukopenia (39% vs. 14%), and, of lesser importance, increased liver enzymes and hypokalemia. These abnormalities improved 2 months after transplantation when the sirolimus target trough level was lowered from 30 to 15 ng/ml. Occurrence of cytomegalovirus was comparable (14% vs. 12%); incidences of herpes simplex (24% vs. 10%, P=0.08) and pneumonia (17% vs. 2%, P=0.03) were higher with sirolimus. No gingival hyperplasia was seen with sirolimus, tremor was rare, and hypertension was less frequent (17% vs. 33%). Two malignancies were observed with CsA and none with sirolimus. Conclusions. Results at 12 months suggest that sirolimus can be used as base therapy in the prophylaxis of acute renal transplant rejection, and has a safety profile that differs from CsA.
878 citations
TL;DR: Rapamycin is a new antifungal antibiotic produced by Streptomyces hygroscopicus NRRL 5491. It was isolated from mycelium by solvent extraction, purified by silica gel column chromatography and crystallized as a colorless solid which melts at 183 approximately to 185 degrees C and has the empirical formula C56H89NO14 as discussed by the authors.
Abstract: Rapamycin is a new antifungal antibiotic produced by Streptomyces hygroscopicus NRRL 5491. It was isolated from the mycelium by solvent extraction, purified by silica gel column chromatography and crystallized as a colorless solid which melts at 183 approximately to 185 degrees C and has the empirical formula C56H89NO14. From its characteristic ultraviolet absorption spectrum rapamycin can be classified as a triene. It is highly active against various Candida species, especially Candida albicans. Its activity is compared with that of amphotericin B, candicidin and nystatin.
862 citations