Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report the case of a 41-year old patient who underwent orthotopic liver transplantation because of decompensated liver cirrhosis due to chronic HCV-infection. Severe acute allograft rejection was insufficiently controlled by cyclosporine A, steroids and a 6-day regimen of OKT 3 monoclonal antibody therapy. As a consequence immunosuppressive therapy was switched to FK 506 in a dose of 3 mg bid. The FK 506 concentration in whole blood consistently ranged between 5.1 and 7.8 ng/ml. Seven weeks after the onset of FK 506 therapy the patient developed severe diabetes mellitus with fasting blood glucose levels up to 640 mmol/l. The C-peptide was elevated reflecting a higher than normal insulin secretion. Intravenous insulin therapy with application of up to 85 units regular insulin per day was initiated. Because of the severe diabetes immunosuppression was changed back to cyclosporine A. After six weeks the patient did no longer require insulin and showed an entirely normal glucose tolerance test, C-peptide and Hb A1-level. This case shows that the diabetogenic side effect of FK 506 is more pronounced than that of cyclosporine A. We propose to change immunosuppressive therapy to cyclosporine A in cases of FK 506 induced severe diabetes mellitus, since long-term prognosis of many transplant recipients may depend on side effects of the immunosuppressive agents.
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PMID:Complete reversal of FK 506 induced diabetes in a liver transplant recipient by change of immunosuppression to cyclosporine A. 865 88

Cyclosporine (CsA) and FK506 are structurally unrelated immunosuppressants, but function in similar ways. FK506 and rapamycin (RAPA), on the other hand, have structural similarities, but act by different mechanisms to yield immunosuppression. Besides their immunosuppressive action, CsA and FK506 are known to interfere with T-cell development. CsA treatment after lethal X-irradiation and syngeneic bone marrow transplantation results in autoimmune disease, which is referred to as CsA-induced autoimmunity. In this study, we examined the effect of RAPA on T-cell development by flow cytometry and immunohistochemistry in female Lewis and Brown Norway rats. Irradiation and syngeneic bone marrow transplantation were performed before a 4-week course of RAPA administration to determine de novo T-cell development in relation to possible autoimmune phenomena. RAPA interfered with the maturation of thymocytes to the CD4+CD8+ DP stage, which resulted in a relative increase in TCRalphabeta(-) immature thymocytes, localized in a rim along the outer cortex. The thymus of RAPA-treated animals had a thinner cortex, leading to stronger thymic atrophy. In the periphery, only a few T cells were observed at the end of RAPA treatment. In the Lewis rat, a normal CD4/CD8 T-cell ratio and an increased Th1/Th2 ratio was observed within the T-cell population. Six weeks after cessation of RAPA therapy, the T-cell compartment was restored to normal, with respect to number and phenotype. In Brown Norway rats, however, T-cell areas were barely detectable at the end of RAPA treatment. The CD4/CD8 T-cell ratio was decreased as a result of a lower number of CD4 T cells; the Th1/Th2 ratio was increased but Th2 remained higher. Similar to Lewis rats, the situation was almost normalized 6 weeks after cessation of RAPA administration. However, Brown Norway rats, in contrast to Lewis rats, showed T-cell infiltration and concomitant induction of MHC class II in the submandibular salivary gland, as well as insulitis, in the pancreas. Possible relationships to Sjogren's disease and diabetes remain to be established.
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PMID:Effect of in vivo rapamycin treatment on de novo T-cell development in relation to induction of autoimmune-like immunopathology in the rat. 887 95

Until recently, FK 506 was used only for rescue therapy after pancreas transplantation. We report our initial experience with FK 506 for 67 pancreas recipients (treated between 1 May 1993 and 30 April 1995). Of these recipients, 49 (73%) received FK 506 for induction and maintenance therapy, 12 (18%) for rescue or antirejection therapy, and 6 (9%) for reasons other than rescue or antirejection therapy. In our induction and maintenance therapy group, 32 recipients (65%) underwent a simultaneous pancreas-kidney transplant (SPK), 8 (16%) a pancreas transplant alone (PTA), and 9 (19%) a pancreas after previous kidney transplant (PAK). Quadruple immunosuppression was used for induction; the median FK 506 starting dose was 4 mg/day p.o. and target levels were 10-20 ng/ml. The most common side effects were nephrotoxicity (16%) and neurotoxicity (14%); transient episodes of hyperglycemia were also noted (12%), in particular in the presence of concurrent rejection and infection episodes. A matched-pair analysis was done to compare graft outcome with FK 506 versus cyclosporin A (CsA). For SPK recipients, pancreas graft survival at 6 months was 79% with FK 506 versus 65% with CsA (P = 0.04), for PTA, 100% versus 63% (P > 0.35), and for PAK, 88% versus 33% (P > 0.01). Pancreas graft loss due to rejection at 6 months posttransplant was lower with FK 506 versus CsA. Two FK 506 recipients died from B-cell lymphomas (Epstein-Barr virus positive) at 6 and 7 months posttransplant. In our rescue or anti-rejection group, 5 recipients underwent SPK, 3 PTA, and 4 PAK. The mean average FK 506 dose was 10 mg/day p.o. and the mean average FK 506 blood level was 11 ng/ml. The most common side effects were nephrotoxicity (33%) and neurotoxicity (16%). Two recipients developed hyperglycemic episodes, of whom 1 has remained on insulin with good exocrine pancreas graft function. Graft survival at 6 months after conversion was 75% for SPK, 67% for PTA, and 50% for PAK. Only one graft was lost due to chronic rejection. Our single-center experience shows that FK 506 after pancreas transplantation is associated with: (1) a low rate of graft loss due to rejection when used for induction, in particular for solitary pancreas transplants, (2) a high rate of graft salvage when used for rescue, (3) a 1% rate of new-onset insulin-dependent diabetes mellitus, and (4) a 3% rate of posttransplant lymphoma. Further studies are necessary to analyze the long-term impact of FK 506 on pancreas transplant outcome.
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PMID:Use of FK 506 in pancreas transplantation. 895 41

FK506 (tacrolimus) is an immunosuppressive drug which interrupts Ca2+-calmodulin-calcineurin signaling pathways in T lymphocytes, thereby blocking antigen activation of T cell early activation genes. Regulation of insulin gene expression in the beta cell may also involve Ca2+-signaling pathways and FK506 has been associated with insulin-requiring diabetes mellitus during clinical use. The purpose of this study was to characterize the effects of FK506 on human insulin gene transcription, insulin mRNA levels, and insulin secretion using as a model the HIT-T15 beta cell line. FK506 had no acute effect on insulin secretion in the HIT cell, but caused a reversible time- and dose-dependent (10(-9)-10(-6) M) decrease in HIT cell insulin secretion. Decreased insulin secretion in the presence of FK506 was also accompanied by a dose-dependent decrease in HIT cell insulin content, insulin mRNA levels, and expression of a human insulin promoter-chloramphenicol acetyl transferase (CAT) reporter gene. FK506 decreased HIT cell expression of the human insulin promoter-CAT reporter gene by 40% in the presence of both low (0.4 mM) at high (20 mM) glucose concentrations. Western blot analysis of HIT cell proteins gave evidence for the presence of calcineurin in the HIT cell. These findings suggest that FK506 may have direct effects to reversibly inhibit insulin gene transcription, leading to a decline in insulin mRNA levels, insulin synthesis, and ultimately insulin secretion.
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PMID:Effects of tacrolimus (FK506) on human insulin gene expression, insulin mRNA levels, and insulin secretion in HIT-T15 cells. 898 25

Tacrolimus was used as the primary immunosuppressive agent in 69 pediatric renal transplantations between December 17, 1989, and June 30, 1995. Children undergoing concomitant or prior liver and/or intestinal transplantation were excluded from analysis. The mean recipient age was 10.3+/-5.0 years (range, 0.7-17.5 years). Seventeen (24.6%) children were undergoing retransplantation, and six (8.7%) had a panel reactive antibody level of 40% or higher. Thirty-nine (57%) cases were with cadaveric kidneys, and 30 (43%) were with living donors. The mean donor age was 28.0+/-14.7 years (range, 1.0-50.0 years), and the mean cold ischemia time for the cadaveric kidneys was 27.0+/-9.4 hr. The antigen match was 2.7+/-1.2, and the mismatch was 3.1+/-1.2. All patients received tacrolimus and steroids, without antibody induction, and 26% received azathioprine as well. The mean follow-up was 32+/-20 months. One- and 4-year actuarial patient survival rates were 100% and 95%. One- and 4-year actuarial graft survival rates were 99% and 85%. The mean serum creatinine level was 1.2+/-0.8 mg/dl, and the calculated creatinine clearance was 82+/-26 ml/min/1.73 m2. The mean tacrolimus dose was 0.22+/-0.14 mg/ kg/day, and the level was 9.5+/-4.8 ng/ml. The mean prednisone dose was 2.1+/-4.9 mg/day (0.07+/-0.17 mg/kg/day), and 73% of successfully transplanted children were off prednisone. Seventy-nine percent were not taking any antihypertensive medications. The mean serum cholesterol level was 158+/-54 mg/dl. The incidence of delayed graft function was 4.3%. The incidence of rejection was 49%, and the incidence of steroid-resistant rejection was 6%. The incidence of rejection decreased to 27% in the most recent 26 cases (January 1994 through June 1995). The incidence of new-onset diabetes was 10.1%; six of the seven affected children were able to be weaned off insulin. The incidence of cytomegalovirus disease was 13%, and that of posttransplant lymphoproliferative disorder was 10%; the incidence of posttransplant lymphoproliferative disorder in the last 40 transplants was 5% (two cases). All of the children who developed posttransplant lymphoproliferative disorder are alive and have functioning allografts. Based on this data, we believe that tacrolimus is a superior immunosuppressive agent in pediatric renal transplant patients, with excellent short- and medium-term patient and graft survival, an ability to withdraw steroids in the majority of patients, and, with more experience, a decreasing rate of rejection and viral complications.
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PMID:Tacrolimus in pediatric renal transplantation. 899 Mar 56

Leflunomide (Lef) is a novel immunosuppressant that can prevent islet allograft and xenograft rejection. In this study, we investigated the in vivo effects of Lef on the function of normal pancreatic islets and syngeneic islet grafts in rats and compared its effect to cyclosporine (CsA) and FK506. Different groups of rats were treated with Lef (10 and 20 mg/kg/day), CsA (20 mg/kg/day), or FK506 (2 mg/kg/day). After 4 and 6 weeks, nonfasting blood glucose (BG) levels of all the treatment groups were not different from that of the control group. Intravenous glucose tolerance test revealed that the rate of glucose disappearance was normal in Lef-treated groups. However, the rate of glucose disappearance in the CsA- and FK506-treated rats was impaired. In contrast, long-term (7 months) treatment of rats with CsA (10 mg/kg/day) resulted in five of seven rats developing hyperglycemia. However, normal BG was observed in all rats treated for 7 months with Lef (10 mg/kg/day). In the second experimental model, streptozocin-induced diabetic ACI rats were grafted with an average of 1200 syngeneic islets into the liver or kidney capsule. Diabetes in these ACI recipients was stably reversed for 6 months, then these rats were treated with Lef (20 mg/kg/day), CsA (20 mg/kg/day), and FK506 (2 mg/kg/day). After 14 days of treatment, nonfasting BG levels were significantly increased in rats treated with CsA (before: 105 +/- 2.9 mg/ dl, after: 275.8 +/- 60 mg/dl) as well as in rats treated with FK506 (before: 108 +/- 2.4 mg/dl, after: 209 +/- 10.1 mg/dl). In contrast, the BG levels of the Lef-treated rats were indistinguishable from those of the untreated control groups. Site of transplantation, i.e., liver and kidney, did not affect the results. Our results indicating that Lef has no diabetogenic property in vivo lends support to the promise that leflunomide may be effective for clinical islet transplantation.
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PMID:In vivo effects of leflunomide on normal pancreatic islet and syngeneic islet graft function. 907 44

Immunosuppressive agents increase the risk of death due to coronary disease or stroke by their ability to cause 3 different adverse effects: dyslipidaemia, hypertension and hyperglycaemia. Post-transplant diabetes mellitus has emerged as a major adverse effect of immunosuppressants. As recipients of organ transplants survive longer, the secondary complications of diabetes mellitus have assumed greater importance. There is a need for a precise definition of post-transplant diabetes mellitus to facilitate inter-centre comparison and to study the natural history of post-transplant diabetes mellitus. We recommend broad criteria to define hyperglycaemia, as a fasting blood glucose level of > 400 mg/dl at any point or > 200 mg/dl for 2 weeks, or a need for insulin treatment for at least 2 weeks. We also recommend serial measurements of HbA1c. Cyclosporin and tacrolimus cause post-transplant diabetes mellitus by a number of mechanisms, including decreased insulin secretion, increased insulin resistance or a direct toxic effect on the beta cell. For corticosteroids, the induction of insulin resistance seems to be the predominant factor. However, few studies have examined the mechanism of diabetogenicity at the molecular level. This may hold the key for pharmacological manipulation of current immunosuppressive regimens which may result in decreased metabolic complications. Corticosteroid sparing regimens have been shown to reduce the metabolic complications of immunosuppressants including post-transplant diabetes mellitus. However, their use should be balanced against the increased incidence of transplant rejections. Post-transplant diabetes mellitus may be organ-specific irrespective of the immunosuppressant used. Tacrolimus causes a high incidence of post-transplant diabetes mellitus in recipients of kidney transplants (upto 20% in some reports); the diabetogenicity of cyclosporin-based regimens is comparable with that of tacrolimus-based regimens in recipients of liver transplants. A few clinical studies in which attempts were made to discontinue cyclosporin resulted in an unacceptable loss of the transplant. In the case of tacrolimus, complete withdrawal of immunosuppression may be possible in selected patients with liver transplants. However, post-transplant recipients who may benefit from this approach are difficult to identify. In some early series, patients received doses of tacrolimus that were approximately 2 to 3 times higher than those currently used, which may have resulted in a higher incidence of post-transplant diabetes mellitus. More recently, it has been shown that tacrolimus was successful in salvaging whole pancreatic grafts which were maintained on cyclosporin. Tacrolimus-based immunosuppression as primary therapy was also used with remarkable success in solitary whole pancreas transplants. Strategies to reduce the metabolic complications of immunosuppressants should be pursued aggressively as this will directly lead to a decrease in long term cardiovascular adverse effects.
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PMID:Post-transplant diabetes mellitus. The role of immunosuppression. 911 92

FK506 a new and potent immunosuppressive agent has been shown to be effective in prolonging pancreatic islet allograft survival. The present study was to determine its efficacy in prolonging pig islet xenotransplantation in two different strains of rat recipients. A total of two dosages of FK506 at 1 or 2 mg/kg per day for 2 weeks and then at weekly intervals were tested as monotherapy for their effect on the survival of renal subcapsular xenografts of purified or impure adult pig islets in inbred ACI and outbred Wistar rats. Histological assessment indicated that FK506 at 2 mg/kg per day significantly prolonged purified pig islet xenograft survival and to 7.5 months in two of three ACI recipients. Monotherapy with a lower dosage of FK506 or transplantation with impure pig islets resulted in increased graft survival time over controls, but less than that with the 2 mg/kg per day FK506. The viable pig islet xenografts showed a normal appearance and were readily identified by immunohistochemical staining for insulin and glucagon and further confirmed by immunohistochemical staining with anti-pig islet specific monoclonal antibody clone P44, developed in our laboratory. Mononuclear cell infiltration, mainly of the CD8-positive T-cell subset, increased with the duration of the graft in the recipient. By 7.5 months the majority of the xenografted islet cells were enclosed by the cellular infiltrate. The in vitro perfusion study of pig islets that had survived for 1 or 2 months in vivo showed that they were responsive to glucose stimulation with increase in insulin secretion into the perfusate. The results demonstrated that FK506 significantly prolonged pig islet survival in two rat strains and suggested that it is an effective immunosuppressant for the xenotransplantation model.
Diabetes Res Clin Pract 1997 Sep
PMID:Prolongation of pig islet xenograft survival in rats immunosuppressed with FK506. 930 35

An unprecedented arsenal of new xenobiotic immunosuppressive agents has been developed recently. Most of the new immunosuppressants have been tested primarily in the treatment of allograft rejection in experimental models of transplantation, and some of the new drugs have already proven their safety and efficiency in extensive clinical trials on transplant patients. Another field for their potential application is the treatment of autoimmune diseases. This review will give an overview of the therapeutic potential of the new xenobiotic drugs in different animal models of rheumatoid arthritis, systemic lupus erythematosus, myasthenia gravis, multiple sclerosis, diabetes mellitus, thyroiditis and uveoretinitis. The new xenobiotics are either inhibitors of the de novo synthesis of nucleotides, for example mycophenolate mofetil, mizoribine, leflunomide, and brequinar, or are immunophilin-binding agents (cyclosporin, FK506 and rapamycin) that inhibit signal transduction and cell cycle progression in lymphocytes. A different mode of action is likely to account for the immunosuppressive effects of deoxyspergualin, which may interfere with intracellular chaperoning by the heat shock protein HSP70 and the activation of transcription factor NF-kappa B.
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PMID:Xenobiotic immunosuppressive agents: therapeutic effects in animal models of autoimmune diseases. 935 1

FK506 (tacrolimus), a potent immunosuppressant, is used for inhibiting allograft rejection in the organ transplantation field. In a preclinical toxicity study in rats, FK506 induced various toxicities, including renal and pancreatic injuries. One of these toxic findings was cataract, and we have found that cataract appeared in rats dosed orally with FK506 for 13 weeks and more. Therefore, to better elucidate the onset mechanism of FK506-induced cataract, we measured biochemical parameters, such as sorbitol, Na,K-ATPase and glutathione in the lens of rats. Rats were dosed with FK506 in oral daily doses of 0.2, 1 or 5 mg/kg for 13 weeks, the lowest dose of which approximated the expected clinical dosage. Cataract developed in the 5-mg/kg/day group, with an incidence of 25%, whereas no cataract formation was observed in the 0.2- or 1-mg/kg/day groups. Five mg/kg/day led an increase of sorbitol and a decrease of reduced type glutathione, but did not affect Na,K-ATPase activity of the lens. FK506 is known to have diabetogenicity mediated through pancreatic injury, which appears as vacuolation of islet cell in rats. Five mg/kg/day of FK506 induced an elevation of blood glucose associated with glucose intolerance, and decrease of both basal insulin level and insulin content in the pancreas, and the changes were in parallel with the cataract development in the present study. On the other hand, diabetic parameters did not change in the 0.2- or 1-mg/kg/day groups. These observation suggest that diabetes developed in the rats dosed with 5 mg/kg/day of FK506. Coadministration of a novel aldose reductase inhibitor, Zenarestat, at an oral dose of 50 mg/kg/day resulted in a reduction of incidence of the FK506-induced cataract and a decrease of sorbitol levels in the lens when compared to that in the lens of rats dosed with 5 mg/kg/day of FK506. These results suggest that FK506-induced cataract in rats is due to an accumulation of sorbitol in the lens, secondary to the diabetogenic effect of FK506. FK506 treatment at the doses of 0.2 and 1 mg/kg/day neither affected parameters indicative of diabetes nor induced cataract in rats, suggesting that the cataract would not develop with FK506 if diabetic parameters were kept under control.
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PMID:Cataract development induced by repeated oral dosing with FK506 (tacrolimus) in adult rats. 935 35


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