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)

Calcineurin inhibitors potentially contribute to risk of cardiovascular events through the development of new-onset diabetes mellitus, hypertension and hyperlipidemia. The exact extent to which calcineurin inhibitors affect these risk factors is difficult to establish since pre-existing renal disease and concomitant immunosuppressive agents (such as steroids or TOR inhibitors) also exert an effect. Clinical trials have consistently shown a higher incidence of new-onset diabetes mellitus with tacrolimus, which has been borne out in large-scale registry analyses. However, the risk of hypertension is approximately 5% higher with cyclosporine than tacrolimus, as is the risk of hyperlipidemia. Statin therapy is effective in treating dyslipidemia and has significant benefits in renal transplant patients. An individualized approach to choice of calcineurin inhibitor, by which cyclosporine or tacrolimus are selected based on the patient's particular risk profile, may thus help to reduce the toll of cardiovascular mortality among renal transplant recipients in the future.
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PMID:Assessing the relative risk of cardiovascular disease among renal transplant patients receiving tacrolimus or cyclosporine. 1577 54

A retrospective chart review of 1065 consecutive liver allograft recipients in 11 centers from January 1997 to September 1998 was performed. Patients were followed for 3 years or until graft loss. Patients received either tacrolimus (n = 594), cyclosporine (n = 450) or no calcineurin inhibitor (n = 21). Model for end-stage liver disease (MELD) scores at time of transplant were similar between the two groups. During follow-up, more patients switched from cyclosporine to tacrolimus (26.7%) than from tacrolimus to cyclosporine (12.8%; p < 0.0001). Patient and graft survival were equivalent. Corticosteroid use was more common in cyclosporine-treated patients (p < 0.00001). Patients receiving tacrolimus experienced lower serum creatinine levels at months 3 through 36 (p < 0.0001). Systolic blood pressure was lower in patients receiving tacrolimus (p < 0.001) despite a reduced requirement for anti-hypertensive agents (p < 0.0001). In addition, tacrolimus was associated with lower total cholesterol and triglyceride levels for months 3 through 24 and 3 through 12, respectively (p < 0.01), despite a reduced requirement for anti-hyperlipidemic agents. The incidence of new-onset diabetes mellitus was similar in both groups. While both calcineurin inhibitors were associated with excellent patient and graft survival, renal function, blood pressure and serum lipid levels were significantly better with tacrolimus treatment.
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PMID:A comparison of tacrolimus and cyclosporine in liver transplantation: effects on renal function and cardiovascular risk status. 1581 94

Liver transplant recipients are at risk of chronic renal failure (CRF), customarily considered to be secondary to CsA/FK506 nephrotoxicity. We have examined renal biopsies from 26 liver transplant recipients with CRF. Before OLT, 5 patients had CRF, 8 were diabetic and 9 hypertensive. Renal biopsies were performed at a mean of 5 years after liver transplantation. Mean SCr was then 212 micromol/L, proteinuria was 1 g/24 h. Twelve patients were diabetic and 25 hypertensive. Histology revealed impressive renal destruction, with a mean of 45% interstitial fibrosis and 45% glomerular sclerosis. All biopsies showed severe arteriosclerosis. CRF can be attributed to four associated primary lesions: (i) specific chronic CsA/FK506 arteriolopathy; (ii) typical diabetic nephropathy; (iii) acute or chronic thrombotic microangiopathy attributed to CsA/FK506 or alpha-IFN and (iv) tubular changes related to administration of hydroxyethylstarch. At the end of the follow-up, after a mean of 6.4 years, 12 patients required dialysis, 13 had CRF and only 1 had normal renal function. Thus, CRF in OLT recipients is more complex than originally thought and should not be classified as anti-calcineurin nephrotoxicity without further investigations, including renal histology. These investigations have therapeutic potential, that is, they may lead to a more aggressive treatment of hypertension and/or diabetes.
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PMID:Renal histopathological lesions after orthotopic liver transplantation (OLT). 1581 74

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

Cyclosporine A (CsA) and tacrolimus have been associated with an increased risk for diabetes after transplantation, whereas sirolimus is deemed to be devoid of any effect on glucose metabolism. This study was performed to investigate the effect of the withdrawal of calcineurin inhibitors and the switch to sirolimus on peripheral insulin resistance and pancreatic beta cell response. Twenty-six patients who received a kidney transplant and discontinued CsA and were converted to sirolimus and 15 recipients of suboptimal kidneys who were treated with tacrolimus plus sirolimus for the first 3 mo after grafting and thereafter with sirolimus alone were enrolled. All patients underwent an oral glucose tolerance test and intravenous insulin tolerance test before and 6 mo after the conversion to sirolimus-alone therapy. The withdrawal of CsA or tacrolimus was associated with a significant fall of insulin sensitivity (both P = 0.01) and with a defect in the compensatory beta cell response, as measured by the disposition index (P = 0.004 and P = 0.02, respectively). The increase of insulin resistance and the decrease of disposition index significantly correlated with the change of serum triglyceride concentration after the conversion to sirolimus-based therapy (R(2) = 0.30, P = 0.0002; and R(2) = 0.19, P = 0.004, respectively). Clinically, the switch to sirolimus was associated with a 30% increase of incidence of impaired glucose tolerance and with four patients' developing new-onset diabetes. In conclusion, the discontinuation of calcineurin inhibitors and their replacement by sirolimus fail to ameliorate the glycometabolic profile of kidney transplant recipients. Rather, it is associated with a worsening of insulin resistance and an inappropriately low insulin response.
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PMID:Glucose metabolism in renal transplant recipients: effect of calcineurin inhibitor withdrawal and conversion to sirolimus. 1610 80

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

The impact of hepatitis C virus on patient and graft survival after renal transplantation remains controversial. However, recent studies have given emphasis on the detrimental role of hepatitis C on long-term patient and graft survival after renal transplantation. Various mechanisms can promote the lower survival in hepatitis C virus-positive recipients, i.e. post-transplant diabetes mellitus, liver disease and infections. Novel evidence has been accumulated showing the inhibitory activity of ciclosporin on the hepatitis C virus replication rate in human hepatocytes; ciclosporin has been shown in vitro to suppress hepatitis C virus replication as effectively as interferon alpha. This effect has not been seen with tacrolimus and is separate from its immunosuppressive activity. Data from patients with normal kidney function or after bone marrow transplantation show that ciclosporin inhibits hepatitis C virus replication. It appears that the progression of liver fibrosis is slower in hepatitis C virus-positive liver transplant recipients treated with ciclosporin than tacrolimus. In contrast, the clinical outcome of hepatitis C in hepatitis C virus-positive patients after liver transplantation treated with ciclosporin vs. tacrolimus has given mixed results. No information after renal transplantation is available. Various parameters can promote the worsening of hepatitis C after renal transplantation but choice of calcineurin inhibition is one of the few risk factors that can potentially be modified by the physician. Prospective, comparative trials of ciclosporin and tacrolimus with large size and adequate follow-up after renal transplantation are in progress.
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PMID:Review article: hepatitis C virus and calcineurin inhibition after renal transplantation. 1619 87

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

The defects identified in the mechanical activity of the hearts from type 1 diabetic animals include alteration of Ca2+ signaling via changes in critical processes that regulate intracellular Ca2+ concentration. These defects result partially from a dysfunction of cardiac ryanodine receptor calcium release channel (RyR2). The present study was designed to determine whether the properties of the Ca2+ sparks might provide insight into the role of RyR2 in the altered Ca2+ signaling in cardiomyocytes from diabetic animals when they were analyzed together with Ca2+ transients. Basal Ca2+ level as well as Ca2+-spark frequency of cardiomyoctes isolated from 5-week streptozotocin (STZ)-induced diabetic rats significantly increased with respect to aged-matched control rats. Ca2+ transients exhibited significantly reduced amplitude and prolonged time courses as well as depressed Ca2+ loading of sarcoplasmic reticulum in diabetic rats. Spatio-temporal properties of the Ca2+ sparks in cardiomyocytes isolated from diabetic rats were also significantly altered to being almost parallel to the changes of Ca2+ transients. In addition, RyR2 from diabetic rat hearts were hyperphosphorylated and protein levels of both RyR2 and FKBP12.6 depleted. These data show that STZ-induced diabetic rat hearts exhibit altered local Ca2+ signaling with increased basal Ca2+ level.
Diabetes 2005 Nov
PMID:Effects of diabetes on ryanodine receptor Ca release channel (RyR2) and Ca2+ homeostasis in rat heart. 1624 29

Obese Zucker rat (OZR) is a genetic model of obesity with noninsulin-dependent diabetes and hypertension. The OZR exhibit hyperinsulinemia, hyperlipidmia, and high circulating glucocorticoid levels. We have shown previously that long-term potentiation (LTP) is impaired in the CA1 region of the hippocampus of OZR. In the present work, although electrophysiological recording from anesthetized OZR hippocampus showed impaired LTP in the CA1, an intact LTP was recorded in the dentate gyrus (DG) region of the hippocampus of the same OZR. Thus, LTP is differentially impaired in the CA1 compared with the DG region of OZR hippocampus. Immunoblotting was used to investigate the molecular mechanism responsible for impairment of LTP in the CA1 but not in the DG region. Analysis revealed reduction in the levels of phosphorylated calcium-dependent calmodulin kinase II (P-CaMKII) and total CaMKII in the CA1 region of OZR. However, in the DG region, reduction was observed only in the levels of total CaMKII, with no change in P-CaMKII levels. The ratio of P-CaMKII to total CaMKII was increased in the DG but not in the CA1 area of hippocampus of OZR. Although unchanged in the CA1, calcineurin levels were significantly reduced in the DG of OZR. These findings suggest that the DG might possess a compensatory mechanism whereby calcineurin levels are reduced to allow sufficient P-CaMKII to produce an apparently normal LTP in the DG area of OZR hippocampus.
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PMID:Impairment of long-term potentiation in the CA1, but not dentate gyrus, of the hippocampus in Obese Zucker rats: role of calcineurin and phosphorylated CaMKII. 1628 Jun 4


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