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)

New-onset diabetes mellitus (NODM) is associated with increased risk of graft failure and death in renal transplant recipients. Some clinical studies have indicated that NODM risk is higher with tacrolimus than cyclosporine, but no comparative trial has used American Diabetic Association (ADA)/World Health Organization (WHO) criteria for diagnosis of diabetes mellitus. The Diabetes Incidence After Renal Transplantation, Neoral C2 Monitoring Versus Tacrolimus (DIRECT) study is a 6-month open-label, multicenter trial comparing the impact of tacrolimus and Neoral (cyclosporine microemulsion) on glucose metabolism in 700 de novo kidney transplant recipients, based on ADA/WHO criteria. Patients are randomized to tacrolimus (C0 monitoring) or Neoral (C2 monitoring), stratified by baseline diabetic status and ethnicity. All patients receive basiliximab, corticosteroids, and mycophenolate mofetil or enteric-coated mycophenolate acid (myfortic). Pooled interim 3-month results from a subset of 115 patients receiving either tacrolimus or Neoral showed that the primary efficacy end-point (biopsy-proven acute rejection [BPAR], graft loss or death) occurred in 11 patients (10%). There were four graft losses and only one death, which occurred after graft loss. Eight patients experienced BPAR (7.3%). Among 99 patients who were nondiabetic at baseline, 14 developed NODM by month 3, 17 developed impaired fasting glucose or impaired glucose tolerance, and another 5 patients received hypoglycemic treatment for at least 14 consecutive days or at the month 3 visit, resulting in a 36% incidence of impaired glucose metabolism. At 3 months, median GFR (Nankivell) was 63.7 mL/min; median serum creatinine was 137 micromol/L. Full complete results are expected in December 2005.
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PMID:Prospective, multicenter, randomized trial to compare incidence of new-onset diabetes mellitus and glucose metabolism in patients receiving cyclosporine microemulsion versus tacrolimus after de novo kidney transplantation. 1584 4

We evaluate 5-year results of a prospective randomized trial that compared cyclosporine microemulsion (CsA-me) and Tacrolimus (Tac) for primary immunosuppression. One hundred one adult patients undergoing liver transplantation were randomized to receive Tac (n = 50) or CsA-me (n = 51). The most frequent indication for the procedure was cirrhosis due to virus C followed by alcoholism. Survival rates at 1, 3, and 5 years were 86%, 75%, and 72%, respectively; there was no significant difference between CsA-me versus Tac arms. Acute rejection occurred in 30 cases (30%), independent of the type of primary immunosuppression. Serious adverse events were reported significantly more among patients under CsA-me (48 episodes) than under Tac (32 episodes). Nineteen patients were switched to the other calcineurin inhibitor. The switch was much more frequent from CsA-me to Tac (n = 15; 29.4%), mainly because of lack of efficacy (n = 10; 19.6%). There were no cases of chronic rejections in the Tac arm. Four patients were switched from Tac to CsA-me for side effects; only 1 remains alive, after treatment was changed from CsA-me to an antimetabolite. There were no statistical differences in renal dysfunction, diabetes, hypertension, neurologic disorders, new-onset malignancies, or infections. There were no differences in survival or rejection among the intention-to-treat groups. Serious adverse events, total patients with switch of calcineurin inhibitor, as well as switches due to lack of efficacy, were statistically more frequent under CsA-me. Tacrolimus seems to be a more appropriate drug to be used for primary immunosuppression in liver transplantation.
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PMID:Five-year follow-up of a trial comparing Tacrolimus and cyclosporine microemulsion in liver transplantation. 1591 41

Tacrolimus was approved in Japan in April 1996 for the prevention of allograft rejection in patients receiving kidney transplants. There has been a concern that immunosuppressive therapy may be associated with cardiovascular and metabolic complications, including hyperlipidemia, hypertension, and posttransplant diabetes mellitus. A multicenter (59 institutions) study was conducted in Japan in patients who underwent renal transplantation and received tacrolimus immunosuppression. Patients were followed for >5 years, from April 1996 to December 2002. Of the 1569 patients enrolled, 1542 were evaluated. In this analysis, graft survival rate and medication usage patterns of antihyperlipidemics, antihypertensives, insulin, and oral hypoglycemics were observed for >5 years in patients receiving tacrolimus immunosuppression. The graft survival rates of patients requiring antihyperlipidemic therapy and experiencing acute rejection were significantly lower compared with all other patients (P < .05). The risk of graft rejection was significantly greater in patients with cardiovascular complications requiring antihyperlipidemics or antihypertensives. Graft survival was significantly lower in patients with acute rejection and antihyperlipidemic therapy than in other patients.
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PMID:Safety analysis after tacrolimus immunosuppression in renal transplant recipients in Japan: 5-year results in >1500 patients. 1591 58

Recent clinical trials have documented the short-term safety of steroid avoidance (SA) in kidney transplant recipients. Since July 2003, we have used a SA immunosuppression protocol for low-risk kidney transplant recipients. Eligibility criteria are age > or = 18, primary transplant (living or deceased donor), and tacrolimus started by postoperative day 3. Recipients were excluded if peak/current PRA was >50%/20%, or if they had a positive flow crossmatch, or if they had the recent use of corticosteroids (<6 months). All recipients received induction with rabbit anti-thymocyte globulin, total dose 6 mg/kg, or basiliximab. Recipients received 5 daily doses of corticosteroid and mycophenolate mofetil 1 gm twice daily starting on the day of transplantation. Tacrolimus was started when the serum creatinine level decreased by 20%, or by postoperative day 3. The goal for trough tacrolimus levels was 10-15 ng/mL for the first month, 8-12 ng/mL for months 2-3, and 5-10 ng/mL after month 3. Protocol biopsies (bx) were performed at reperfusion, 1 month, 4 months, and 12 months. Ninety-four kidney transplantations were performed during the study period. Sixty-seven recipients (71%) were eligible and enrolled in SA. Characteristics of the 67 SA recipients: mean age, 53 years (range, 26-70); 41% female; 67% Caucasian; 24% Hispanic; 15% African American; and 5% Native American. Also, 77% received a living donor kidney. The mean follow-up was 180 days (range, 10-360). At last follow-up, 91% remained steroid-free. Biopsy-proven acute rejection (BPAR) occurred in 5 recipients (7.5%). Three recipients (4.5%) had clinical BPAR and 2 had subclinical. One recipient died with pneumonia 4 months following transplantation. Posttransplantation diabetes mellitus (PTDM) occurred in 2 (5%) of 38 recipients. In the initial 41 recipients, 27 had protocol bx at 1 month and 13 at 4 months available for analysis. Chronic allograft nephropathy (CAN) was present on protocol bx in 48% at 1 month and 69% at 4 month. Actuarial (Kaplan-Meier method) patient and graft survival rates at 351 days were 97.8% and 96.8%, respectively. SA with anti-thymocyte globulin induction in low-immunologic risk kidney transplant recipients is safe and is associated with a low risk of BPAR. The incidence of PTDM appears to be lower.
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PMID:Steroid avoidance immunosuppression in low-risk kidney transplant recipients. 1591 66

Posttransplantation diabetes mellitus (PTDM) is a complication arising mostly during the first 6 months after kidney transplantation. Considering the serious outcomes of chronic hyperglycemia in kidney transplant patients, the recognition of factors that contribute to the onset of PTDM is of particular relevance. A retrospective analysis was performed to document the incidence of and the risk factors for diabetes mellitus occurring in the first year after kidney transplantation among 177 adult patients, without previously known diabetes transplanted between January 1998 and December 2000. PTDM, defined as fasting plasma glucose > or = 126 mg/dL confirmed by repeat testing on a different day, occurred in 48 (27.12%) patients of whom 36 showed transient changes during the first year after transplantation. Univariate analysis identified variables to be associated with the onset of PTDM: older recipient age (P = .05), male gender (P = .03), family history of diabetes (P = .04), advanced donor age (P = .008), absence of induction immunosuppression (P = .04), use of tacrolimus (vs cyclosporine; P = .01), one or more than one (steroid-treated) acute rejection episode(s) (P = .000001), cytomegalovirus infection (P = .02), and use of beta-blockers or diuretics (P = .05). By multivariate analysis, five factors were independently associated with the onset of PTDM: two episodes of rejection (odds ratio = 42.69, P = .000025), one episode of rejection (5.01, P = .007), older recipient age (1.06, P = .017), family history of diabetes (7.24, P = .011), and weight at transplantation (1.03, P = .048). Tacrolimus treatment remained of borderline significance (2.77, P = .05). In addition to traditional risk factors predisposing to the development of type 2 diabetes in the general population, episodes of acute rejection significantly influence the incidence of PTDM.
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PMID:Factors influencing the onset of diabetes mellitus after kidney transplantation: a single French center experience. 1591 84

Cardiovascular morbidity, including coronary artery disease and left ventricular hypertrophy, and mortality are high in patients following renal transplantation. Cardiovascular disease is thought to be due to traditional (hypertension, hyperlipidemia, diabetes mellitus and smoking) as well as nontraditional cardiovascular risk factors (microinflammation). Furthermore, immunosuppressive drugs, namely, calcineurin inhibitors, sirolimus, and steroids, have been reported to adversely affect cardiovascular risk factors (e.g., hypertension, hyperlipidemia, hyperglycemia). Evidence from comparative trials and from conversion studies suggest that blood pressure, hyperlipidemia, and hyperglycemia after renal transplantation may be differentially affected by the calcineurin inhibitors cyclosporine and tacrolimus. In the European Tacrolimus versus Cyclosporin A Microemulsion Renal Transplantation Study, 557 patients were randomly allocated to therapy with tacrolimus (n = 286) versus cyclosporine (n = 271). In addition, to blood pressure, serum cholesterol, HDL cholesterol, triglycerides, and blood glucose, we estimated the 10-year risk of coronary heart disease (Framingham risk score). Tacrolimus resulted in a significantly lower time-weighted average of serum cholesterol (P < .001), and mean arterial blood pressure (P < .05), but a higher time-weighted average of blood glucose (P < .01) than cyclosporine. Mean 10-year coronary artery disease risk estimate was significantly lower in men treated with tacrolimus, (10.0% versus 13.2%; P < .01) but was unchanged in women (4.7% versus 7.0%). Tacrolimus and cyclosporine microemulsion have compound-specific effects on cardiovascular risk factors that differentially affect the predicted rate of coronary artery disease.
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PMID:Cardiovascular risk estimates and risk factors in renal transplant recipients. 1591 88

Early steroid discontinuation (ESD) has been associated with a lower incidence of post-transplant diabetes mellitus (PTDM). We retrospectively reviewed the incidence of PTDM in relation to racial groups in kidney transplant recipients treated with ESD. Between January 2002 and September 2003, 125 consecutive primary adult kidney transplants were performed. Group A (n = 91) had steroids discontinued on postoperative day 6 and maintenance immunosuppression of Tacrolimus and mycophenolate mofetil. Group B (n = 34), received the same immunosuppression but was maintained on steroids indefinitely. Induction consisted of thymoglobulin in African-Americans; all others received Simulect. At 1 yr, patient/graft survival, serum creatinine and rate of acute rejection were similar in both groups. The incidence of PTDM was significantly lower in group A (7%) compared with group B (26%, p = 0.0209). The incidence of PTDM in group A was limited to Hispanic patients with a family history of diabetes mellitus. African-Americans and Caucasians in group A did not experience PTDM (p = 0.005 compared with African-American in group B). Our steroid free protocol nearly eliminated the incidence of PTDM in African-Americans and Caucasians, but was still associated with significant rate of PTDM in Hispanic recipients. Alternative immunosuppression may benefit this population.
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PMID:Increased risk of post-transplant diabetes mellitus despite early steroid discontinuation in Hispanic kidney transplant recipients. 1600

Relaxation of the upper age limits for solid organ transplantation coupled with improvements in post-transplant survival have resulted in greater numbers of elderly patients receiving immunosuppressant drugs such as tacrolimus. Tacrolimus is a potent agent with a narrow therapeutic window and large inter- and intraindividual pharmacokinetic variability. Numerous physiological changes occur with aging that could potentially affect the pharmacokinetics of tacrolimus and, hence, patient dosage requirements. Tacrolimus is primarily metabolised by cytochrome P450 (CYP) 3A enzymes in the gut wall and liver. It is also a substrate for P-glycoprotein, which counter-transports diffused tacrolimus out of intestinal cells and back into the gut lumen. Age-associated alterations in CYP 3A and P-glycoprotein expression and/or activity, along with liver mass and body composition changes, would be expected to affect the pharmacokinetics of tacrolimus in the elderly. However, interindividual variation in these processes may mask any changes caused by aging. More investigation is needed into the impact aging has on CYP and P-glycoprotein activity and expression. No single-dose, intense blood-sampling study has specifically compared the pharmacokinetics of tacrolimus across different patient age groups. However, five population pharmacokinetic studies, one in kidney, one in bone marrow and three in liver transplant recipients, have investigated age as a co-variate. None found a significant influence for age on tacrolimus bioavailability, volume of distribution or clearance. The number of elderly patients included in each study, however, was not documented and may have been only small. It is likely that inter- and intraindividual pharmacokinetic variability associated with tacrolimus increase in elderly populations. In addition to pharmacokinetic differences, donor organ viability, multiple co-morbidity, polypharmacy and immunological changes need to be considered when using tacrolimus in the elderly. Aging is associated with decreased immunoresponsiveness, a slower body repair process and increased drug adverse effects. Elderly liver and kidney transplant recipients are more likely to develop new-onset diabetes mellitus than younger patients. Elderly transplant recipients exhibit higher mortality from infectious and cardiovascular causes than younger patients but may be less likely to develop acute rejection. Elderly kidney recipients have a higher potential for chronic allograft nephropathy, and a single rejection episode can be more devastating. There is a paucity of information on optimal tacrolimus dosage and target trough concentration in the elderly. The therapeutic window for tacrolimus concentrations may be narrower. Further integrated pharmacokinetic-pharmacodynamic studies of tacrolimus are required. It would appear reasonable, based on current knowledge, to commence tacrolimus at similar doses as those used in younger patients. Maintenance dose requirements over the longer term may be lower in the elderly, but the increased variability in kinetics and the variety of factors that impact on dosage suggest that patient care needs to be based around more frequent monitoring in this age group.
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PMID:Pharmacokinetic considerations relating to tacrolimus dosing in the elderly. 1603 70

Insulin-like growth factor-I (IGF-1) ameliorates cardiac dysfunction in diabetes although the mechanism of action remains poorly understood. This study examined the role of PI-3 kinase/Akt/mammalian target of rapamycin (mTOR) and calcineurin pathways in cardiac effects of IGF-1 against glucose toxicity. Adult rat ventricular myocytes were cultured for 8 h with either normal (NG, 5.5 mM) or high (HG, 25.5 mM) glucose, in the presence or absence of IGF-1 (10-500 nM), the PI-3 kinase/Akt inhibitor LY294002 (10 microM), the mTOR inhibitor rapamycin (20 microM) or the calcineurin inhibitors cyclosporin A (5 microM) or FK506 (10 mg/l). Mechanical properties were evaluated using an IonOptix MyoCam system. HG depressed peak shortening (PS), reduced maximal velocity of shortening/relengthening (+/- dl/dt) and prolongs time-to-90% relengthening (TR90), which were abolished by IGF-1 (100 and 500 nM). Interestingly, the IGF-1-elicited protective effect against HG was nullified by either LY294002 or rapamycin, but not by cyclosporine A or FK506. None of the inhibitors affected cell mechanics. Western blot analysis indicated that HG and IGF-1 stimulated phosphorylation of Akt and mTOR. HG also activated p70s6k and suppressed GSK-3beta phosphorylation. However, the HG-induced alterations in phosphorylation of Akt, mTOR, p70s6k and GSK-3beta were significantly reversed by IGF-1. Protein expression of Akt, mTOR, p70s6k, GSK-3beta, SERCA2a and phospholamban was unaffected by HG, IGF-1 or rapamycin. Rapamycin significantly enhanced Akt phosphorylation whereas it inhibited mTOR phosphorylation. Collectively, our data suggest that IGF-1 may provide cardiac protection against glucose in part through a PI-3 kinase/Akt/mTOR/ p70s6k-dependent and calcineurin-independent pathway.
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PMID:Inhibition of PI-3 kinase/Akt/mTOR, but not calcineurin signaling, reverses insulin-like growth factor I-induced protection against glucose toxicity in cardiomyocyte contractile function. 1613 69

Diabetes mellitus causes multiple cardiovascular complications. Previous studies have shown that prolonged exposure (96 h) of human umbilical vein endothelial cells (HUVECs) to hyperglycemia causes a significant increase in apoptosis. We report here that this increase in apoptosis is associated with an increase in Ca(2+) current (whole cell patch-clamp recorded) resulting from Ca(2+) entry mediated by store-operated channels (SOCs). The number of apoptotic cells after prolonged high glucose (HG, 30 mmol/L) exposure was significantly reduced in the presence of the SOC inhibitor 2-APB or of La(3+). A marked increase (approximately 80%) in Ca(2+)-dependent calcineurin (CN-A) phosphatase activity also occurred after prolonged HG exposure. Prolonged HG exposure-induced increase in CN-A activity was prevented by 2-APB, and selective CN-A phosphatase inhibition by FK506 or calmodulin inhibition by calmidazolium decreased HG-induced apoptosis. Blocking hydrogen peroxide production using catalase or inhibiting the tyrosine kinase pp60(src) during prolonged exposure to HG, resulted in a marked decrease in apoptosis and was further associated with a significant reduction in CN-A phosphatase activity. The results demonstrate a significant role for Ca(2+) entry in HG-induced apoptosis in HUVECs, and suggest that this role is mediated via H(2)O(2) generation and the action of the Ca(2+)-activated protein phosphatase calcineurin.
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PMID:High glucose-induced apoptosis through store-operated calcium entry and calcineurin in human umbilical vein endothelial cells. 1624 95


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