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)

Cyclosporin (CsA) therapy is associated with side effects such as hypertension, hyperlipidemia and nephrotoxicity. Tacrolimus (Tac) has been shown to be more favourable in this respect. We retrospectively analysed office blood pressure (BP), serum total cholesterol (TC) and fasting glucose levels, and estimated graft function profiles in paediatric (n =56) and young adult (n =14) renal transplant recipients whose maintenance immunosuppressive regimen was based upon CsA (n =38) or Tac (n =32) given with mycophenolate mofetil and corticosteroids. The analysis was performed at four different time-points: at 1, 6, 12, and 24 months post-transplant, respectively. Baseline characteristics were comparable between treatment groups. Differences for both systolic and diastolic BP, and graft function between treatment groups became significant from month 1 and throughout the 2-year period. Values (mean +/- SD) for CsA-treated and Tac-treated recipients at 2 years were 118.8+/-11.1 / 74.6+/-7.4 mmHg vs 109.3+/-11.2 / 67.2+/-7.8 mmHg for systolic and diastolic BP, respectively, p <0.005/0.005; and 72.0+/-18.5 ml/min vs 84.0+/-22.4 ml/min per 1.73 m(2) for graft function, respectively, p <0.01. Office hypertension, defined as the use of antihypertensive medication at month 24, was significantly associated with CsA-therapy (chi(2), p <0.01). TC levels became significantly lower at months 6, 12, and 24 in the Tac group compared with the CsA group. Hypercholesterolemia, defined as TC>or=200 mg/dl, was significantly associated with CsA-based immunosuppressive regimen at months 6, 12, and 24 post-transplant (chi(2), p <0.05, p <0.001, and p <0.01, respectively). Although Tac therapy was associated with higher glucose levels, no recipient developed post-transplant diabetes mellitus. The number of recipients who experienced acute rejections was comparable in both groups. In conclusion, Tac-based immunosuppressive therapy was found to be associated with more favourable potential risk-factor profiles for cardiovascular disease and better graft function at 2 years post-transplant compared with CsA-therapy.
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PMID:Potential cardiovascular risk factors in paediatric renal transplant recipients. 1625 6

Posttransplantation diabetes mellitus (PTDM) is a common complication of kidney transplantation, associated with poorer graft and patient outcomes. Tacrolimus is a strong immunosuppressive drug associated with low acute rejection rates, but a higher risk for PTDM. High trough levels of tacrolimus during the first month after transplantation have been found to be a significant risk factor for the development of PTDM. The aim of this single-center study was to identify the risk factors for the development of PTDM among kidney transplant recipients under tacrolimus therapy. We examined 73 cadaveric kidney transplant recipients receiving tacrolimus between 1994 and 2003. Age, donor and recipient gender, dialysis method, body mass index (BMI), first year weight gain, mismatches, incidence of acute rejection and delayed graft function, hepatitis C serology, first year cumulative steroid dose, first tacrolimus blood level, first tacrolimus blood level <15 ng/mL, and corresponding tacrolimus daily doses and concentration/dose ratios (CDR) were also collected. PTDM was defined as at least 2 fasting blood glucose values > or =126 mg/dL, according to the World Health Organization criteria. Incidence of first year PTDM was 27.4%. Patients with PTDM showed significantly higher age, BMI, first tacrolimus blood level, first tacrolimus CDR, and CDR with tacrolimus blood level <15 ng/mL as well as less 1-year weight gain. After logistic regression, age (relative risk [RR] 1.060, confidence interval [CI] 95%, 1.001-1.122; P = .043) and first tacrolimus blood level (RR 1.154; CI 95%, 1.038-1.283; P = .008) remain significant risk factors for developing PTDM. Older age and initial tacrolimus blood levels were the main risk factors for PTDM among our group of patients. Kidney transplant recipients who develop PTDM maintain a high CDR of tacrolimus.
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PMID:Higher initial tacrolimus blood levels and concentration-dose ratios in kidney transplant recipients who develop diabetes mellitus. 1638 49

It is suggested that specific methods of Tacrolimus monitoring rather than immunoassays which over-estimate Tacrolimus levels, should be used in transplant recipients. There is limited data, however, comparing clinical outcomes of renal transplantation using each of these techniques. In this study, 40 renal transplant recipients with Tacrolimus monitoring by Microparticle Enzyme Immunoassay (MEIA; target trough level 10-15 ng/ml) were compared with 40 patients monitored by High Performance Liquid Chromatography with Tandem Mass Spectrometry (HPLC-MS; target trough level 8-13 ng/ml). All received anti CD25 antibody induction and Mycophenolate Mofetil in a steroid sparing protocol. No demographic differences were seen between MEIA and HPLC-MS groups. All patients were followed for 6 months. Patient survival was 100% in both groups; graft survival was 100% in the MEIA group and 97.5% in the HPLC-MS group. The groups did not differ in the number of dose changes required in the first 6 months or in the number of patients displaying Tacrolimus levels within target range at three and six months. Delayed graft function occurred in 14 patients in the MEIA group and 12 patients in the HPLC-MS group (P = NS). Biopsy-proven acute rejection occurred in 4 patients in the MEIA group and 1 patient in the HPLC-MS group (P = 0.17). Biopsy proven acute Tacrolimus nephrotoxicity occurred in 6 patients in the MEIA group, and 7 in the HPLC-MS group (P = NS). No difference was seen in serum creatinine or estimated creatinine clearance at 3 or 6 months. No difference between groups was seen in systolic or diastolic blood pressure, or total cholesterol at 3 or 6 months. 2 patients in the MEIA group developed CMV disease and 1 developed posttransplantation diabetes mellitus. CMV and posttransplantation diabetes were not seen in the HPLC-MS group. 2 patients in each group developed reversible tremor. This study suggests that renal transplantation with HPLC-MS monitoring of Tacrolimus is safe and effective.
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PMID:Clinical outcomes of renal transplantation using liquid chromatographic monitoring of tacrolimus. 1662 43

Glucocorticoid excess induces hyperglycemia, which may result in diabetes. The present experiments explored whether glucocorticoids trigger apoptosis in insulin-secreting cells. Treatment of mouse beta-cells or INS-1 cells with the glucocorticoid dexamethasone (0.1 micromol/l) over 4 days in cell culture increased the number of fractionated nuclei from 2 to 7 and 14%, respectively, an effect that was reversed by the glucocorticoid receptor antagonist RU486 (1 micromol/l). In INS-1 cells, dexamethasone increased the number of transferase-mediated dUTP nick-end labeling-staining positive cells, caspase-3 activity, and poly-(ADP-) ribose polymerase protein cleavage; decreased Bcl-2 transcript and protein abundance; dephosphorylated the proapoptotic protein of the Bcl-2 family (BAD) at serine155; and depolarized mitochondria. Dexamethasone increased PP-2B (calcineurin) activity, an effect abrogated by FK506. FK506 (0.1 micromol/l) and another calcineurin inhibitor, deltamethrin (1 micromol/l), attenuated dexamethasone-induced cell death. The stable glucagon-like peptide 1 analog, exendin-4 (10 nmol/l), inhibited dexamethasone-induced apoptosis in mouse beta-cells and INS-1 cells. The protective effect of exendin-4 was mimicked by forskolin (10 micromol/l) but not mimicked by guanine nucleotide exchange factor with the specific agonist 8CPT-Me-cAMP (50 micromol/l). Exendin-4 did not protect against cell death in the presence of cAMP-dependent protein kinase (PKA) inhibition by H89 (10 micromol/l) or KT5720 (5 micromol/l). In conclusion, glucocorticoid-induced apoptosis in insulin-secreting cells is accompanied by a downregulation of Bcl-2, activation of calcineurin with subsequent dephosphorylation of BAD, and mitochondrial depolarization. Exendin-4 protects against glucocorticoid-induced apoptosis, an effect mimicked by forskolin and reversed by PKA inhibitors.
Diabetes 2006 May
PMID:Dexamethasone induces cell death in insulin-secreting cells, an effect reversed by exendin-4. 1664 95

A systematic review of randomized clinical trials (RCT) was undertaken to evaluate the beneficial and harmful effects of immunosuppression with cyclosporin versus tacrolimus for liver transplanted patients. MEDLINE, EMBASE, Cochrane Central and Hepato-Biliary Group Controlled Trials Registers were searched. Using fixed and random effects model, relative risk (RR), values <1 favoring tacrolimus, with 95% confidence intervals (CI) were calculated. Of 717 potentially relevant references, 16 RCTs were eligible for inclusion. Mortality and graft loss at 1 year were significantly reduced in tacrolimus-treated recipients (Death: RR 0.85, 95% CI 0.73-0.99; graft loss: RR 0.73, 95% CI 0.61-0.86). Tacrolimus reduced the number of recipients with acute rejection (RR 0.81, 95% CI 0.75-0.88) and steroid-resistant rejection (RR 0.54, 95% CI 0.47-0.74) in the first year. Lymphoproliferative disorder or dialysis rates were not different but more de novo diabetes (RR 1.38, 95% CI 1.01-1.86) occurred with tacrolimus. More patients stopped cyclosporin than tacrolimus (RR 0.57, 95% CI 0.49-0.66). Treating 100 recipients with tacrolimus instead of cyclosporin would avoid rejection and steroid-resistant rejection in nine and seven patients respectively, graft loss and death in five and two patients respectively, but four additional patients would develop diabetes after liver transplantation.
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PMID:Cyclosporin versus tacrolimus as primary immunosuppressant after liver transplantation: a meta-analysis. 1682 58

Clinical trials have consistently shown a higher incidence of new-onset diabetes mellitus with tacrolimus than cyclosporine. However, in protocol-driven studies steroid doses are comparable in both treatment arms, while in clinical practice steroid dose used in conjunction with tacrolimus or cyclosporine may differ. This retrospective study analysed renal transplant recipients without pre-existing diabetes receiving tacrolimus (n = 100) or cyclosporine (n = 100) for whom one-year follow-up data were available. Diabetes was defined as use of insulin or oral hypoglycemic agents; fasting glucose >6.9 mmol/L; or non-fasting glucose >11 mmol/L on three consecutive occasions. Tacrolimus-treated patients were significantly older than cyclosporine-treated patients (49 +/- 14 vs. 44 +/- 13 yr, p < 0.05) and received a significantly lower cumulative dose of corticosteroids over the first three months post-transplant (1284 +/- 379 vs. 1714 +/- 486 mg, p < 0.0001). At 3, 6, 9 and 12 months significantly more tacrolimus-treated patients had new-onset diabetes than cyclosporine- treated patients. At 12 months, 18 patients receiving tacrolimus and two receiving cyclosporine had diabetes (p < 0.0001). There was a clear relationship between age and incidence of new-onset diabetes at three months in the tacrolimus cohort. After stratifying patients by age group, the frequency of diabetes was significantly higher with tacrolimus than with cyclosporine in patients aged 40-60 yr [8/46 (17.4%) vs. 2/48 (4.2%), p < 0.05] and >60 yr [9/28 (32.1%) vs. 0/14 (0%), p < 0.05]. The mean tacrolimus trough level during the first three months was similar in patients with diabetes (13.1 +/- 2.3 ng/mL) or without diabetes (13.0 +/- 2.8 ng/mL, n.s.). These results indicate that new-onset diabetes is strongly and significantly associated with tacrolimus vs. cyclosporine in renal transplant recipients, even when steroid dosing is lower with tacrolimus.
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PMID:Relative risk of new-onset diabetes during the first year after renal transplantation in patients receiving tacrolimus or cyclosporine immunosuppression. 1696 94

Stimulation of local renin-angiotensin system and increased levels of oxidants characterize the diabetic heart. Downregulation of ANG II type 1 receptors (AT(1)) and enhancement in PKC activity in the heart point out the role of AT(1) blockers in diabetes. The purpose of this study was to evaluate a potential role of an AT(1) blocker, candesartan, on abnormal Ca(2+) release mechanisms and its relationship with PKC in the cardiomyocytes from streptozotocin-induced diabetic rats. Cardiomyocytes were isolated enzymatically and then incubated with either candesartan or a nonspecific PKC inhibitor bisindolylmaleimide I (BIM) for 6-8 h at 37 degrees C. Both candesartan and BIM applied on diabetic cardiomyocytes significantly restored the altered kinetic parameters of Ca(2+) transients, as well as depressed Ca(2+) loading of sarcoplasmic reticulum, basal Ca(2+) level, and spatiotemporal properties of the Ca(2+) sparks. In addition, candesartan and BIM significantly antagonized the hyperphosphorylation of cardiac ryanodine receptor (RyR2) and restored the depleted protein levels of both RyR2 and FK506 binding protein 12.6 (FKBP12.6). Furthermore, candesartan and BIM also reduced the increased PKC levels and oxidized protein thiol level in membrane fraction of diabetic rat cardiomyocytes. Taken together, these data demonstrate that AT(1) receptor blockade protects cardiomyocytes from development of cellular alterations typically associated with Ca(2+) release mechanisms in diabetes mellitus. Prevention of these alterations by candesartan may present a useful pharmacological strategy for the treatment of diabetic cardiomyopathy.
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PMID:Restoration of diabetes-induced abnormal local Ca2+ release in cardiomyocytes by angiotensin II receptor blockade. 1701 47

This report described an interim analysis of a investigator-driven multicenter trial in renal transplant recipients: the Prospective Quality of life Renal Transplantation Switch Study; Tacrolimus-based immunosuppression ("PQRST study"). Patients included in the trial initially treated with cyclosporine-based immunosuppression after renal transplantation who experienced side effects, such as hypertension, hyperlipidemia, hypertrichosis, or other adverse reactions, were converted to a tacrolimus-based immunosuppressive regimen (n = 31). Steroids were subsequently discontinued between 3 and 6 months after the conversion. As of today 19/31 (50%) patients have been successfully weaned off steroids with the remaining patients in this process. In this interim analysis, with a follow-up ranging from 1 to 18 months both patient and graft survivals were 100%. No patient experienced an acute rejection episode; none of the grafts were lost. Blood pressure decreased in 22/31 (71%) of the patients. No patient developed de novo diabetes or other serious side effect related to the conversion. Three patients were withdrawn from the trial because of side effects: bleeding, depression, and proteinuria. However, none of these adverse events were felt to be directly related to the change of the immunosuppressive regimen to tacrolimus monotherapy. In conclusion, conversion from cyclosporine to tacrolimus-based therapy was safe and well tolerated; it may improve the cardiovascular risk profile after kidney transplantation.
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PMID:Steroid-free immunosuppression in kidney transplant recipients and prograf monotherapy: an interim analysis of a prospective multicenter trial. 1709 29

Cardiovascular risk factors after kidney transplantation are enhanced as a result of the chronic use of immunosuppressants. Tacrolimus with mycophenolate mofetil has become the most commonly used combination after kidney transplantation. Cardiovascular risk factors that are related to the use of this combined therapy have been analyzed in various clinical trials in comparison with other immunosuppressive therapies. This review summarizes the main results of these studies regarding arterial hypertension, lipid profile, posttransplantation diabetes, renal function, and even acute rejection rate. The aim is to characterize the cardiovascular risk profile of tacrolimus and mycophenolate mofetil association when compared with older and newer immunosuppressive associations.
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PMID:Impact of tacrolimus and mycophenolate mofetil combination on cardiovascular risk profile after kidney transplantation. 1713 Feb 78

Clinical protocols in type 1 diabetic patients to optimize islet survival and function post-transplantation improved dramatically in the last decade, but it is clear that this approach still has potential limitations to provide long term insulin independency. Islet allografts administered in the liver via the portal vein are exposed to several factors contributing to a rapid loss of function that may reach 50% of the initial beta cell mass. Allo- and auto-immune reactions - an unique situation in clinical transplantation - are partially overcome with immunosuppressive regimen. Serological markers and T cell reactivities may correlate with graft failure. Most of the drugs that are used, including rapamycin (sirolimus) or the calcineurin inhibitor tacrolimus (FK506), have deleterious effects on beta function and/or insulin sensitivity. Immediate factors that limit initial islet engraftment have been elucidated, including instant blood mediated inflammatory reaction and angiogenesis. Newer interventions designed to promote islet survival, to prevent apoptosis, to promote islet growth and to protect islets in the long run from immunological injury are rapidly approaching clinical trials.
Diabetes Metab 2006 Dec
PMID:Immunology of pancreatic islet transplantation. 1713 Aug 11


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