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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Immunosuppression is currently used for allotransplantation, and is being evaluated for the treatment of insulin-dependent diabetes mellitus and other autoimmune diseases. However, most available agents have a number of side effects that limit their use in clinical situations. It has been shown previously, for example, that cyclosporine may inhibit insulin release from islet tumor cells and rat islets. We have studied the effects of an analog of a newer agent (FK506) termed L-683,590 on insulin secretion by an islet tumor line, beta TC3, and rat islets, and compared the effects of this drug to those of cyclosporine, since both cause similar immunosuppression. L-683,590 and cyclosporine inhibited insulin release by beta TC3 cells by about 50% and 80%, respectively, at doses that inhibit lymphokine production by T cells. The inhibition by L-683,590 and cyclosporine was more pronounced at higher glucose levels, and was not simply attributable to a general toxic effect of the drugs on the cells. Insulin release during long-term (> 48 hr) cultures of isolated rat islets was also inhibited by the drugs. However, there was no effect of either agent on insulin release by islets during the first 4 hr following a glucose stimulus. Both drugs caused reduced levels of insulin mRNA (by 56 +/- 8.1% and 66 +/- 16% in the presence of L-683,590 and cyclosporine, respectively), accounting for reduced rates of insulin biosynthesis that were also seen. Our studies indicate that: (1) both cyclosporine and L-683,590 inhibit insulin release by beta TC3 cells and cultured rat islets after 48 hr (cyclosporine is a more potent inhibitor); (2) neither drug inhibits the release of insulin during the first 4 hr following a glucose stimulus; and (3) their mechanisms of action appear to be similar--both drugs cause reduced levels of insulin mRNA. Although the toxicity of FK506 on human islets in vivo is still unknown, it may be of particular importance in individuals with impaired beta cell function, such as patients with new-onset insulin-dependent diabetes or patients with non-insulin-dependent diabetes mellitus.
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PMID:Inhibition of glucose-stimulated insulin release from beta TC3 cells and rodent islets by an analog of FK506. 767 56

FK 506 was used as a primary immunosuppressive agent in 125 cases of renal transplantation in a randomized trial comparing FK 506/prednisone with FK 506/azathioprine/prednisone. With a mean follow-up of 5.5 +/- 2.5 months, there has been a 6-month actuarial patient survival of 99% and graft survival of 88%. There is no difference thus far between the two-drug and three-drug groups, although there may be less rejection and diabetes in the three-drug group. These results suggest that FK 506 is a useful immunosuppressive agent in kidney transplantation.
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PMID:Randomized trial of FK 506/prednisone vs FK 506/azathioprine/prednisone after renal transplantation: preliminary report. 767 36

We investigated the preventive effect of the immunosuppressive agent FK506 on autoimmune insulitis in nonobese diabetic mice. The mice were given FK506 in a dose of 1.0 mg/kg, every other day, from age 2 to 12, 2 to 6, and 4 to 12 weeks, respectively; after which, the incidence of insulitis and overt diabetes was monitored. Effects of FK506 on immune reactions to beta cells were also investigated by using both syngeneic and allogeneic islet transplants. Treatment with FK506 in mice from age 2 weeks prevented completely the onset of overt diabetes, and the incidence of insulitis was reduced to less than 10% at age 30 weeks. Treatment of mice with FK506 from age 4 weeks was less effective in preventing insulitis and the onset of diabetes. In case of islet transplantation, FK506 treatment of NOD mice from age 2 to 6 weeks prevented autoimmune responses both in syngeneic islets and in allogeneic islets, which share the same H-2 antigen with the nonobese diabetic mouse. These results also indicate that the recognition of islet antigens and the generation of autoimmune-reactive T lymphocytes start between 2 and 4 weeks of age, and FK506 prevents an autoimmune reaction.
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PMID:Prevention of insulitis and diabetes in nonobese diabetic mice by administration of FK506. 768 40

Previously we demonstrated prevention of immune rejection in rat islet allografts by continuous subcutaneous (s.c.) administration of FK506 and also showed that FK506 might have diabetogenic effects (Ryu and Yasunami (1991) Transplantation, 52, 599-605). The purpose of the present study was to characterize further diabetogenic effects of FK506 on renal subcapsular islet isografts in rat. Continuous s.c. administration of FK506 (3 mg/kg/day) for 35 days produced glucose intolerance in the recipients as demonstrated by intravenous (i.v.) glucose tolerance test at the end (35 days) and after discontinuation (90 days) of FK506 administration. Morphologically, beta cells in the grafts of FK506-treated group were degranulated at 35 and 120 days after transplantation. Electron microscopically, degranulation, marked swelling of rough endoplasmic reticulum, Golgi apparatus and mitochondria were detected in beta cells of the grafts treated with FK506 at 35 days, and at 120 days there was moderate structural recovery in the organella. These findings clearly demonstrate that FK506 has diabetogenic effects on renal subcapsular islet isografts in rat and also suggests potential reversibility of damages by FK506 in beta cells of the grafts.
Diabetes Res Clin Pract 1993 Apr
PMID:Diabetogenic effects of FK506 on renal subcapsular islet isografts in rat. 768 76

FK506, a agent extracted from a streptomyces, has more potent immunosuppressive properties compared with cyclosporin in vitro. We compared the preventive effect of FK506 on the development of diabetes mellitus with that of cyclosporin in BB rats, which are regarded as a useful model of insulin-dependent diabetes mellitus. BB rats aged 30 days were treated intramuscularly with FK506 (0.1 mg/kg/day and 0.32 mg/kg/day) or with cyclosporin (10 mg/kg, alternate days) until 150 days of age. Diabetes developed in 2 (10.5%) of 19 rats treated with the lower dose of FK506 and none of 20 rats with the higher dose of FK506; on the other hand, 1 (5.3%) of 19 rats treated with cyclosporin developed diabetes. In contrast, 9 (36.0%) of 25 control rats became diabetic. The cumulative incidence of diabetes mellitus in the group treated with FK506 (0.32 mg/kg) showed a decrease similar to or more than that of the cyclosporin-treated group. Histological examination showed that FK506 and cyclosporin prevented the reduction in the average size of islets and in the area of beta cells. The analysis of lymphocyte subsets proved the decrease of W3/25: OX8 ratio in both FK506- and cyclosporin-treated groups. These data suggest that the administration of FK506 might be a more useful tool for preventing the development of insulin-dependent diabetes mellitus.
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PMID:Effect of FK506 on the development of diabetes in BB rats in comparison with that of cyclosporin. 769 21

Postoperative diabetes is a reported feature of the immunosuppressive agents cyclosporin A and FK 506. To date, however, no randomized comparative studies of the metabolic effects of these two drugs have been performed. In this study, extended (300 min) oral glucose tolerance tests (75 g) were performed a median of 8 mo (range 5-9 mo) postoperatively in 20 clinically stable liver transplant recipients randomly allocated to maintenance immunosuppression with either cyclosporin A (with or without azathioprine) or FK 506. None of the patients had clinically overt diabetes antedating transplantation. To avoid the confounding effects of corticosteroids, prednisolone was withdrawn at least 6 wk beforehand in each case. Ten healthy volunteers matched for age and body mass index served as control subjects. Overall blood glucose concentrations after the glucose challenge were significantly elevated in both groups of transplant recipients (P < 0.005 and P < 0.001 for cyclosporin A and FK 506 treatment groups, respectively) compared with the healthy control subjects. Venous whole-blood glucose concentration (mean +/- SE) 120 min after the ingestion of oral glucose was significantly higher in both the cyclosporin A (P < 0.05) and FK 506 (P < 0.01) treatment groups compared with the control subjects (6.6 +/- 0.5 vs. 8.8 +/- 0.9 vs. 5.2 +/- 0.2 mM, respectively). According to 1985 WHO criteria, 4 of 10 cyclosporin A-treated patients had impaired glucose tolerance, whereas 3 of 10 FK 506-treated patients had diabetes with 4 others having impaired glucose tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1993 Dec
PMID:Metabolic effects of cyclosporin A and FK 506 in liver transplant recipients. 769 79

The growing success of organ transplantation for the treatment of diabetes mellitus and end-stage renal, heart, lung, and liver disease is attributable, in part, to improvements in immunosuppressive regimens. This article reviews the immune response and the mechanism by which many immunosuppressants exert their effects. Immunosuppressants discussed include azathioprine, glucocorticoids, cyclosporine A, cyclosporine G, FK506, rapamycin, mycophenolic acid, mycophenolate mofetil (RS-61443), mizoribine (bredinin), brequinar sodium, and deoxyspergualine. The efficacy and nonspecificity of these agents has led to significant side effects from their use, which can be predicted based on their mechanisms of action. The development and use of more specific immunosuppressants or the design of protocols, which would induce organ tolerance, may result in long-term organ survival without infectious or malignant complications.
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PMID:Immunosuppressive drugs and their effects. 801 74

The introduction of new techniques for the determination of renal parenchymal oxygenation and intrarenal microcirculation has elucidated some important aspects in the pathophysiology of acute renal failure (ARF). Data accumulated over the last decade with these techniques, together with improved morphologic evaluation of the kidney, indicate that medullary damage may play a pivotal role in various forms of acute and chronic renal hypoxic and toxic insults. The outer medulla functions normally under hypoxic conditions, as a result of limited regional oxygen supply and high oxygen consumption for urinary concentration. Outer medullary oxygenation is critically balanced by mechanisms designed to adjust oxygen demand and supply, and their insufficiency may lead to ARF with hypoxic medullary damage. In this article, we outline our current concept of the physiologic control of medullary oxygenation and review the clinical conditions that predispose to hypoxic medullary damage, including rhabdomyolysis, hypercalcemia, or the exposure to endotoxin, nonsteroidal anti-inflammatory drugs, radiologic contrast agents, cyclosporine, FK506, and amphothericin. We shall indicate a possible role for medullary oxygen insufficiency in clinical conditions known to predispose to ARF, such as preexisting renal disease, diabetes mellitus, hypertension, atherosclerosis, effective volume depletion, urinary obstruction, or aging, and suggest potential strategies to preserve medullary oxygenation and integrity.
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PMID:The role of medullary ischemia in acute renal failure. 857 90

Between May 1, 1993 and April 5, 1995, 154 pancreas allograft recipients at 9 institutions were given FK506 posttransplant. Three groups were studied: (1) recipients given FK506 initially for induction and maintenance therapy (n = 82), (2) recipients switched to FK506 for antirejection or rescue therapy (n = 61), and (3) recipients converted to FK506 for other reasons (n = 11). Of 82 patients in the induction group, 7 (9%) had simultaneous bone marrow (BM) and pancreas-kidney (SPK-BM) transplants, 54 (66%) had SPK transplants without BM, 14 (17%) had pancreas transplants alone (PTA), and 7 (9%) had pancreas after previous kidney transplants (PAK). All but 1 recipient was given quadruple immunosuppression (anti-T cell agents plus azathioprine and prednisone) for induction. The median FK506 starting dose was 4 mg/day p.o.; the median average FK506 blood level, 12 ng/ml. The most common side effects were neurotoxicity (16%), nephrotoxicity (13%), and gastrointestinal toxicity (9%). New-onset diabetes mellitus requiring permanent insulin therapy did not occur. Of 61 transplants in the rescue group, 44 (72%) were SPK, 11 (18%) PTA, and 6 (10%) PAK. All but 3 (95%) of the recipients had been on cyclosporine-azathioprine-prednisone triple immunosuppression before substitution of FK506 for cyclosporine; 46% of the recipients had one, and 54% > or = 2, rejection episodes preconversion. The most common side effects were nephrotoxicity (25%), neurotoxicity (23%), and gastrointestinal toxicity (21%). Two recipients were reconverted to cyclosporine because of transient hyperglycemia, and one recipient is on insulin. In the induction group, patient survival at 6 months was 90% for SPK, 100% for PTA, and 100% for PAK. According to a matched-pair analysis, pancreas graft survival for SPK recipients at 6 months was 87% for FK506 versus 70% for cyclosporine recipients (P = 0.04); for PTA recipients, 84% versus 66% (P = n.s.); and for PAK recipients, 80% versus 14% (P = 0.11). When technical failures and death with functioning grafts were censored, pancreas graft survival remained significantly better in the FK506 group. The incidence of first reversible rejection episodes by 6 months in FK506 recipients was 35% for SPK, 40% for PTA, and 20% for PAK. Of 75 pancreas grafts, 64 are currently functioning; in 5 recipients the pancreas failed (1 from rejection); 6 recipients died with a functioning pancreas graft. There were 3 posttransplant lymphomas (all EBV-positive); 2 recipients died and 1 is alive after subtotal colectomy and transplant pancreatectomy. In the antirejection rescue group, patient survival rates at 6 months were 91% for SPK, 100% for PTA, and 80% for PAK (P = n.s.). Pancreas graft survival rates at 6 months were 90% for SPK, 72% for PTA, and 40% for PAK. The incidence of first reversible rejection episodes after conversion to FK506 at 6 months was 44% in SPK, 54% in PTA, and 50% in PAK. Of 61 pancreas grafts, 51 are currently functioning; in 7 recipients the pancreas failed (5 from rejection); 3 recipients died with a functioning graft. There were no posttransplant lymphomas in the rescue group. This multicenter survey shows that FK506 in pancreas transplantation is associated with (1) a low rate of graft loss from rejection when used for induction therapy, (2) a high rate of graft salvage when used for rescue or rejection therapy, and (3) a very low rate of new-onset insulin-dependent diabetes mellitus. These encouraging results are tarnished by 3 posttransplant lymphomas in the induction group; a possible explanation is overimmunosuppression, but further (randomized) studies are necessary to analyze the long-term risk-benefit ratio of FK506 after pancreas transplantation.
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PMID:A multicenter analysis of the first experience with FK506 for induction and rescue therapy after pancreas transplantation. 860 Jun 35

Three cases of insulin-requiring diabetes mellitus associated with tacrolimus (FK506) therapy in pediatric renal transplant patients are presented. New-onset diabetes mellitus has been reported with tacrolimus therapy post liver and kidney transplants in up to 12% of adult patients, but is thought to be rare in pediatrics. Although insulin requirement with tacrolimus therapy has been occasionally reported in adolescent patients post liver transplant, only a single case in a pediatric kidney transplant recipient has been previously documented. These cases illustrate the significant diabetogenic effect of tacrolimus in pediatric renal transplant patients. As the use of tacrolimus becomes more prevalent in pediatric kidney transplantation, pediatric nephrologists should be aware of this potential complication.
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PMID:Diabetes as a complication of tacrolimus (FK506) in pediatric renal transplant patients. 861 59


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