tacrolimus and Diabetes-Mellitus--Type-2

The combination of insulin resistance and β-cells dysfunction leads to the onset of type-2 diabetes mellitus (T2DM). This process can last for decades, as β-cells are able to compensate the demand for insulin and maintain normoglycemia. Understanding the adaptive capacity of β-cells during this process and the causes of its failure is essential to the limit onset of diabetes. Post-transplant diabetes mellitus (PTDM) is a common and serious disease that affects 30% of renal transplant recipients. With the exception of immunosuppressive therapy, the risk factors for T2D are the same as for PTDM: obesity, dyslipidaemia, insulin resistance and metabolic syndrome. Tacrolimus (TAC) is the immunosuppressant of choice after renal transplantation but it has the highest rates of PTDM. Our group has shown that insulin resistance and glucolipotoxicity, without favouring the appearance of apoptosis, modify key nuclear factors for the maintenance of identity and functionality of β-cells. In this context, TAC accelerates or enhances these changes. Our hypothesis is that the pathways that are affected in the progression from pre-diabetes to diabetes in the general population are the same pathways that are affected by TAC. So, TAC can be considered a tool to study the pathogenesis of T2DM. Here, we review the common pathways of β-cells dysfunction on T2DM and TAC-induced diabetes.

Topics: Animals; Diabetes Mellitus, Type 2; Humans; Insulin Resistance; Insulin-Secreting Cells; Kidney Transplantation; Tacrolimus; Transplant Recipients

New-onset diabetes mellitus after transplantation (NODAT) is a frequent complication in kidney allograft recipients. It may be caused by modifiable and non-modifiable factors. The non-modifiable factors are the same that may lead to the development of type 2 diabetes in the general population, whilst the modifiable factors include peri-operative stress, hepatitis C or cytomegalovirus infection, vitamin D deficiency, hypomagnesemia, and immunosuppressive medications such as glucocorticoids, calcineurin inhibitors (tacrolimus more than cyclosporine), and mTOR inhibitors. The most worrying complication of NODAT are major adverse cardiovascular events which represent a leading cause of morbidity and mortality in transplanted patients. However, NODAT may also result in progressive diabetic kidney disease and is frequently associated with microvascular complications, eventually determining blindness or amputation. Preventive measures for NODAT include a careful assessment of glucose tolerance before transplantation, loss of over-weight, lifestyle modification, reduced caloric intake, and physical exercise. Concomitant measures include aggressive control of systemic blood pressure and lipids levels to reduce the risk of cardiovascular events. Hypomagnesemia and low levels of vitamin D should be corrected. Immunosuppressive strategies limiting the use of diabetogenic drugs are encouraged. Many hypoglycemic drugs are available and may be used in combination with metformin in difficult cases. In patients requiring insulin treatment, the dose and type of insulin should be decided on an individual basis as insulin requirements depend on the patient's diet, amount of exercise, and renal function.

Topics: Calcineurin Inhibitors; Diabetes Mellitus; Diabetes Mellitus, Type 2; Humans; Immunosuppressive Agents; Kidney Transplantation; Risk Factors; Tacrolimus

Endoplasmic reticulum (ER) stress is a situation caused by the accumulation of unfolded proteins in the endoplasmic reticulum, triggering an evolutionary conserved adaptive response termed the unfolded protein response. When adaptation fails, excessive and prolonged ER stress triggers cell suicide. Important roles for ER-initiated cell death pathways have been recognized for several diseases, including diabetes, hypoxia, ischemia/reperfusion injury, neurodegenerative and heart diseases. The implication of the ER stress is not well recognized in solid organ transplantation, but increasing evidence suggests its implication in mediating allograft injury. The purpose of this review is to summarize the mechanisms of ER stress and to discuss its implication during tissue injury in solid organ transplantation. The possible implications of the ER stress in the modifications of cell functional properties and phenotypic changes are also discussed beyond the scope of adaptation and cell death. Increasing the understanding of the cellular and molecular mechanisms of acute and chronic allograft damages could lead to the development of new biomarkers and to the discovery of new therapeutic strategies to prevent the initiation of graft dysfunction or to promote the tissue regeneration after injury.

Topics: Animals; Apoptosis; Cyclosporine; Diabetes Mellitus, Type 2; Drug Delivery Systems; Endoplasmic Reticulum; Graft Survival; Humans; Insulin Resistance; Islets of Langerhans; Kidney Transplantation; Liver Transplantation; Mice; Organ Preservation; Postoperative Complications; Reperfusion Injury; Tacrolimus; Transplantation; Transplantation, Homologous; Unfolded Protein Response

The most prominent side effect of tacrolimus is the induction of posttransplant diabetes mellitus (PTDM). In this review, the authors discuss the incidence, mechanism, prevention, and treatment of tacrolimus-induced PTDM in renal patients.

Topics: Diabetes Mellitus, Type 2; Humans; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Risk Factors; Tacrolimus

Legionella micdadei (Pittsburgh pneumonia agent) is the second most common cause of Legionella pneumonia, and occurs predominantly in immunocompromised hosts. L micdadei is the cause of nosocomial pneumonia in renal transplant recipients, but has not been described in other adult solid organ transplant recipients. This report describes the first case of L micdadei pneumonia in an adult liver transplant recipient on immunosuppressive therapy. Importantly, this case highlights the difficulties in establishing the diagnosis, as the Legionella urinary antigen is negative, and special culture conditions are required. Furthermore, this case illustrates several atypical clinical features of L micdadei pneumonia in a transplant recipient, including a community acquired mode of transmission, occurrence several years after organ transplantation, and lung abcess formation. The patient was successfully treated with limited surgical resection and quinolone antimicrobial monotherapy.

Topics: Adult; Anti-Infective Agents; Bronchoalveolar Lavage Fluid; Ciprofloxacin; Diabetes Mellitus, Type 2; Hepatitis B; Humans; Immunosuppressive Agents; Legionellosis; Liver Transplantation; Lung Abscess; Male; Pneumonia, Bacterial; Postoperative Complications; Tacrolimus; Tomography, X-Ray Computed

Topical corticosteroids (TCS), used to treat atopic dermatitis (AD), have been associated with type 2 diabetes and osteoporosis in epidemiological studies, possibly explained by systemic absorption.. We examined whether intensive daily whole-body TCS treatment over 2 weeks followed by twice weekly application for 4 weeks could elicit insulin resistance and increase bone resorption in adults with AD.. A randomized parallel-group double-blind double-dummy non-corticosteroid-based active comparator study design was completed in Copenhagen, Denmark. Thirty-six non-obese, non-diabetic adults with moderate-to-severe AD were randomized to whole-body treatment with betamethasone 17-valerate 0.1% plus a vehicle once daily or tacrolimus 0.1% twice daily after washout. Insulin sensitivity assessed by the hyperinsulinemic-euglycemic clamp combined with tracer infusions and biomarkers of bone formation (P1NP) and resorption (CTX) were evaluated at baseline, after 2 weeks of daily treatment and after further 4 weeks of twice-weekly maintenance treatment.. AD severity improved with both treatments and systemic inflammation was reduced. After 2 weeks, we observed similar increase in peripheral insulin sensitivity with use of betamethasone (n = 18) and tacrolimus (n = 18). Bone resorption biomarker, CTX, was unchanged, while bone formation marker, P1NP, decreased after betamethasone treatment after both 2 and 6 weeks but remained unchanged in the tacrolimus arm.. Whole-body treatment with TCS leads to systemic exposure but appears not to compromise glucose metabolism during short-term use, which may be a result of reduced systemic inflammatory activity. The negative impact on bone formation could be regarded an adverse effect of TCS.

Topics: Adrenal Cortex Hormones; Adult; Betamethasone; Dermatitis, Atopic; Dermatologic Agents; Diabetes Mellitus, Type 2; Double-Blind Method; Glucocorticoids; Homeostasis; Humans; Insulin Resistance; Tacrolimus; Treatment Outcome

Calcineurin-inhibitors and hepatitis C virus (HCV) infection increase the risk of post-transplant diabetes mellitus. Chronic HCV infection promotes insulin resistance rather than beta-cell dysfunction. The objective was to elucidate whether a conversion from tacrolimus to cyclosporine A affects fasting and/or dynamic insulin sensitivity, insulin secretion or all in HCV-positive renal transplant recipients.. In this prospective, single-center study 10 HCV-positive renal transplant recipients underwent 2h-75g-oral glucose tolerance tests before and three months after the conversion of immunosuppression from tacrolimus to cyclosporine A. Established oral glucose tolerance test-based parameters of fasting and dynamic insulin sensitivity and insulin secretion were calculated. Data are expressed as median (IQR).. After conversion, both fasting and challenged glucose levels decreased significantly. This was mainly attributable to a significant amelioration of post-prandial dynamic glucose sensitivity as measured by the oral glucose sensitivity-index OGIS [422.17 (370.82-441.92) vs. 468.80 (414.27-488.57) mL/min/m2, p = 0.005), which also resulted in significant improvements of the disposition index (p = 0.017) and adaptation index (p = 0.017) as markers of overall glucose tolerance and beta-cell function. Fasting insulin sensitivity (p = 0.721), insulinogenic index as marker of first-phase insulin secretion [0.064 (0.032-0.106) vs. 0.083 (0.054-0.144) nmol/mmol, p = 0.093) and hepatic insulin extraction (p = 0.646) remained unaltered. No changes of plasma HCV-RNA levels (p = 0.285) or liver stiffness (hepatic fibrosis and necroinflammation, p = 0.463) were observed after the conversion of immunosuppression.. HCV-positive renal transplant recipients show significantly improved glucose-stimulated insulin sensitivity and overall glucose tolerance after conversion from tacrolimus to cyclosporine A. Considering the HCV-induced insulin resistance, HCV-positive renal transplant recipients may benefit from a cyclosporine A-based immunosuppressive regimen.. ClinicalTrials.gov NCT02108301.

Topics: Adult; Blood Glucose; Cyclosporine; Diabetes Mellitus, Type 2; Glomerular Filtration Rate; Glucose Tolerance Test; Graft Rejection; Hepatitis C; Humans; Immunosuppressive Agents; Insulin; Insulin Resistance; Kidney Transplantation; Liver; Middle Aged; Prospective Studies; Risk Factors; RNA, Viral; Tacrolimus; Transplant Recipients

Post-transplantation hypomagnesemia is common and predicts diabetes. Magnesium improves glycemic control in diabetics and insulin sensitivity in insulin resistant subjects. We aimed to assess the effectiveness of oral magnesium for improving glycemic control and insulin sensitivity at 3 months post-transplantation. We conducted a single-center, open-label, randomized parallel group study. We included adults with serum magnesium <1.7 mg/dl within 2 weeks after kidney transplantation. We randomized participants to 450 mg magnesium oxide up to three times daily or no treatment. The primary endpoint was the mean difference in fasting glycemia. Secondary endpoints were the mean difference in area under the curve (AUC) of glucose during an oral glucose tolerance test and insulin resistance measured by Homeostasis Model of Assessment-Insulin Resistance (HOMA-IR). Analyses were on intention-to-treat basis. In patients randomized to magnesium oxide (N = 27) versus no treatment (N = 27), fasting glycemia on average was 11.5 mg/dl lower (95% CI 1.7 to 21.3; P = 0.02). There was no difference between the two groups neither for 2 h AUC, where the mean value was 1164 mg/dl/min (95% CI -1884 to 4284; P = 0.45) lower in the treatment group nor for HOMA-IR. Magnesium supplements modestly improved fasting glycemia without effect on insulin resistance. Higher baseline glycemia among patients in the control group may have driven the positive outcome (ClinicalTrials.gov number: NCT01889576).

Topics: Adult; Aged; Area Under Curve; Blood Glucose; Calcineurin Inhibitors; Diabetes Mellitus, Type 2; Diarrhea; Female; Glucose Tolerance Test; Graft vs Host Disease; Humans; Insulin Resistance; Kidney Failure, Chronic; Kidney Transplantation; Magnesium; Magnesium Deficiency; Magnesium Oxide; Male; Middle Aged; Postoperative Complications; Prediabetic State; Receptor, Insulin; Severity of Illness Index; Tacrolimus

The calcineurin inhibitors cyclosporine and tacrolimus are implicated in post-transplant complications such as new-onset diabetes after transplantation. The relative contribution of each calcineurin inhibitor to new-onset diabetes after transplantation remains unclear. We sought to compare the impact of cyclosporine and tacrolimus on glucose metabolism in humans.. Eight haemodialysis patients received 8-10 days of oral treatment followed by 5-h infusions with cyclosporine, tacrolimus and saline in a randomized, investigator-blind, crossover study. Glucose metabolism and β-cell function was investigated through: a hyperinsulinaemic-euglycaemic clamp, an intravenous glucose tolerance test and insulin concentration time series.. Cyclosporine and tacrolimus decreased insulin sensitivity by 22% (P = 0.02) and 13% (P = 0.048), respectively. The acute insulin response and pulsatile insulin secretion were not significantly affected by the drugs.. In conclusion, 8-10 days of treatment with cyclosporine and tacrolimus impairs insulin sensitivity to a similar degree in haemodialysis patients, while acute insulin responses and pulsatile insulin secretion remain unaffected.

Topics: Body Mass Index; Calcineurin; Cross-Over Studies; Cyclosporine; Denmark; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Insulin; Insulin Secretion; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Tacrolimus

Donor age, calcineurin inhibitor nephrotoxicity, and acute rejection are the most significant predictors of chronic allograft nephropathy. Protocol biopsies, both in deceased- and living-donor renal grafts, have shown that cortical tubulointerstitial fibrosis correlates with graft survival and function. The impact of not treating subclinical acute rejection (SAR) is less clear. In this study, 126 de novo renal transplant recipients were randomly assigned to receive area-under-the-curve-controlled exposure of either a cyclosporine or a tacrolimus-based immunosuppressive regimen that included steroids, mycophenolate mofetil, and basiliximab induction. Protocol biopsies were taken before and 6 and 12 mo after transplantation. The prevalence of SAR was determined retrospectively. Fibrosis was evaluated by quantitative digital analysis of Sirius red staining in serial biopsies. Donor age correlated significantly with tubulointerstitial fibrosis in pretransplantation biopsies and inferior graft function at month 6 (rtau = -0.26; P = 0.033). Acute rejection incidence was 11.5%, and no clinical late rejection occurred. The prevalence of SAR at 6 mo was 30.8% but was not associated with differences in serial quantitative Sirius red staining at 6 or 12 mo, proteinuria, or progressive loss of GFR up to 2 yr. No differences were found in donor variables, histocompatibility, rejection history, or exposure of immunosuppressants. Controlled individualized calcineurin inhibitor exposure and subsequent tapering resulted in a low early acute rejection rate and prevented late acute rejection. Because, by design, we did not treat SAR, these results provide evidence that asymptomatic infiltrates in 6-mo surveillance biopsies may not be deleterious in the intermediate term. There is need for reliable biomarkers to prove that not all cell infiltrates are equivalent or that infiltrates may change with time.

Topics: Adult; Area Under Curve; Biopsy; Calcineurin Inhibitors; Cyclosporine; Diabetes Mellitus, Type 2; Female; Fibrosis; Graft Rejection; Graft Survival; Humans; Kidney; Kidney Transplantation; Male; Middle Aged; Tacrolimus

Type 2 diabetes mellitus is a common problem in patients after solid organ transplantation. We studied the safety and efficacy of pioglitazone therapy in this setting. Ten patients with diabetes mellitus treated with insulin or glyburide after transplantation were studied after the addition of the thiazolidinedione pioglitazone. Serum creatinine, HBA1C, total daily insulin dose, tacrolimus dose, tacrolimus level and prednisone dose were followed for a mean of 242 days and compared to the corresponding values measured before the initiation of pioglitazone. The addition of pioglitazone caused no significant changes in serum creatinine or mean tacrolimus dose, and caused decreases in HBA1C (8.36%+/- 1.5% pre-pioglitazone, 7.08%+/- 1.5% post-pioglitazone, p = 0.018) and total daily insulin dose (125.1 +/- 28.1 units pre-pioglitazone, 80.6 +/- 22.8 units post-pioglitazone, p = 0.002). Our preliminary study suggests that pioglitazone is a safe and effective oral agent for the management of diabetes mellitus after transplantation.

Topics: Adult; Aged; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Immunosuppressive Agents; Kidney Transplantation; Liver Transplantation; Male; Middle Aged; Pioglitazone; Tacrolimus; Thiazolidinediones

The development of diabetes mellitus (DM) after living donor kidney transplantation (KT) is a risk factor for worsening transplant kidney function, cardiac disease, and cerebrovascular disease, which may affect prognosis after KT. At our institution, all patients' glucose tolerance is evaluated perioperatively by oral glucose tolerance tests (OGTTs) at pre-KT, and 3, 6, and 12 month (mo.) after KT. We analyzed the insulinogenic index (ISI) and homeostasis model assessment beta cell (HOMA-β) based on the immunoreactive insulin (IRI) levels to determine how glucose tolerance changed after KT in 214 patients who had not been diagnosed with DM before KT. In addition, we analyzed the body mass index (BMI) which may also influence glucose tolerance after KT. The concentration of tacrolimus (TAC) in blood was also measured as the area under the curve (AUC) to examine its effects at each sampling point. The preoperative-OGTTs showed that DM was newly diagnosed in 22 of 214 patients (10.3%) who had not been given a diagnosis of DM by the pre-KT fasting blood sugar (FBS) tests. The glucose tolerance was improved in 15 of 22 DM patients at 12 mo. after KT. ISI and IRI deteriorated only at 3 mo. after KT but improved over time. There was a trend of an inverse correlation between HOMA-β and TAC-AUC. We also found inverse correlations between IRI and an increase in BMI from 3 to 12 mo. after KT. Early corticosteroid withdrawal or the steroid minimization protocol with tacrolimus to maintain a low level of diabetogenic tacrolimus and BMI decrease after KT used by our hospital individualizes lifestyle interventions for each patient might contribute to an improvement in post-KT glucose tolerance.

Topics: Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; East Asian People; Glucose; Humans; Insulin; Insulin Resistance; Kidney Transplantation; Steroids; Tacrolimus

Sodium/glucose co-transporter-2 inhibitor (SGLT2i) or dipeptidyl peptidase IV inhibitor (DPP4i) is a newer anti-diabetic drug in type II diabetes mellitus (DM), but their use in tacrolimus (TAC)-induced DM is still undetermined. We performed this study to evaluate the effect of these two drugs in TAC-induced DM and nephrotoxicity in ex vivo and in vivo. In the experimental Sprague Dawley rat model of TAC-induced DM and nephrotoxicity, dual inhibition of DPP4 and SGLT2 significantly decreased blood glucose level, HbA1C and increased plasma insulin levels and pancreatic islet size compared with each drug. In the kidney, dual inhibition improved renal function decreased interstitial fibrosis and profibrotic cytokines compared with DPP4i and SGLT2i alone. Increased oxidative stress by TAC was remarkably decreased with DPP4i or SGLT2i in serum, pancreatic and renal tissues and this decrease was much more significant in the combination group. In in vitro study, TAC decreased the cell viability of human kidney-2(HK-2) cells and insulin-secreting beta-cell-derived line(INS-1) cells. SGLT2i protected TAC-induced cell death in HK-2 cells, but not in INS-1 cells. The addition of DPP4i to SGLT2i compensated for a lack of protective effect of SGLT2i on INS-1 cells. This finding provides the rationale for the combined treatment of SGLG2i and DPP4i in TAC-induced DM and nephrotoxicity.

Topics: Animals; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Hypoglycemic Agents; Insulins; Rats; Rats, Sprague-Dawley; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Tacrolimus

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Glucose Tolerance Test; Rats; Rats, Wistar; Tacrolimus

This study aimed to assess posttransplant changes in insulin sensitivity and β-cell function of pancreas transplant recipients according to the type of diabetes mellitus (DM) and the pretransplant insulin sensitivity measured by the Matsuda Index (MI).. We analyzed 60 patients who underwent pancreas transplantation and oral glucose tolerance test pretransplant and at 1 month posttransplant.. At 1 month posttransplant, insulin sensitivity did not show significant improvement; particularly, the MI was significantly lower after transplant in recipients with type 1 DM (T1DM) and those with pretransplant MI of 5 or greater. β-cell function was significantly improved after transplant in all recipients regardless of the type of DM and pretransplant MI values. Glucose control was significantly improved in recipients with T1DM and in all recipients regardless of the pretransplant MI values. Additional oral glucose tolerance test at 1 year posttransplant revealed that insulin sensitivity remained unimproved and β-cell function was higher compared with pretransplant. Glucose control had partially reverted to pretransplant levels in recipients with T1DM and those with pretransplant MI of 5 or greater.. Unlike β-cell function and glucose control, insulin sensitivity did not significantly improve until posttransplant 1 year after pancreas transplantation regardless of the type of DM or the degree of pretransplant insulin sensitivity.

Topics: Adult; Blood Glucose; Calcineurin Inhibitors; Cyclosporine; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Glucagon; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin-Secreting Cells; Kaplan-Meier Estimate; Male; Middle Aged; Pancreas Transplantation; Tacrolimus

Posttransplant diabetes mellitus (PTDM) affects up to 50% of solid organ transplant recipients and compromises long-term outcomes. The goal of this study was to investigate how immunosuppressants affect gene expression in a manner that increases diabetes risk, by performing integrative analysis on publicly available, high-throughput gene expression data.. All high-throughput gene expression datasets of solid organ transplant recipients were retrieved from the Gene Expression Omnibus. Significantly dysregulated genes and pathways were determined, and those in common with type 2 diabetes were identified. THP-1 and HepG2 cells were exposed in vitro to tacrolimus, and validation of genes involved in insulin signaling and glucose metabolism was performed using specific arrays. These cells were then treated with the hypoglycemic agents, metformin, and insulin to assess for appropriate reversion of specific diabetogenic genes.. Insulin signaling and secretion were the most commonly dysregulated pathways that overlapped with diabetes in transplant recipients. KRAS, GRB2, PCK2, BCL2L1, INSL3, DOK3, and PTPN1 were among the most significantly upregulated genes in both immunosuppression and diabetes subsets and were appropriately reverted by metformin as confirmed in vitro.. We discovered that the significantly dysregulated genes in the context of immunosuppression are implicated in insulin signaling and insulin secretion, as a manifestation of pancreatic β-cell function. In vitro validation confirmed key diabetes-related genes in the context of immunosuppression. Further analysis and in vitro validation revealed that metformin optimally reverts diabetogenic genes dysregulated in the context of immunosuppression. The optimal therapeutic management of posttransplant diabetes mellitus needs to be further investigated, taking into account the mechanistic impact of immunosuppressants.

Topics: Datasets as Topic; Diabetes Mellitus, Type 2; Down-Regulation; Gene Expression Profiling; Graft Rejection; Hep G2 Cells; Humans; Hypoglycemic Agents; Immunosuppressive Agents; Insulin; Metformin; Organ Transplantation; Signal Transduction; Tacrolimus; THP-1 Cells; Up-Regulation

Post-transplant diabetes mellitus (PTDM) is a serious and frequent metabolic complication after the transplantation of solid organs. PTDM incidence 12 months after the transplantation is 2.5%-25%.. It is a retrospective analysis with 6-month follow-up of patients after liver transplantation without diabetes mellitus type 1 or 2 at the time of transplantation. We recorded all known risk factors for PTDM; however, only patients with tacrolimus in standard immunosuppression protocol were included in the analysis.. The PTDM incidence in the group of 102 patients was 18.6%. We identified following independent risk factors for PTDM: alcohol-related liver disease (Hazard Ratio 1.8261 [1.2246-2.723], P = .0031) and average level of tacrolimus ≥ 10 ng/mL (2.5482 [1.1592-5.6019], P = .0199). PTDM was diagnosed in average 2.5 months after the liver transplantation.. PTDM leads to infections, cardiovascular disease, and decreased survival. The mechanism by which alcohol-related liver disease influences the development of PTDM remains unclear.

Topics: Adult; Diabetes Mellitus, Type 2; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Liver Diseases, Alcoholic; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Risk Factors; Tacrolimus

Tacrolimus (FK506)-induced diabetes mellitus is one of the most important factors of post-transplant diabetes mellitus (PTDM). However, the detailed mechanisms underlying PTDM are still unclear. Farnesoid X receptor (FXR) regulates glycolipid metabolism. The objective of this study was to explore whether FXR is involved in the development of tacrolimus-induced diabetes mellitus.. After C57BL/6J mice were treated with tacrolimus (FK506) for 3 months, the fasting blood glucose levels, body weights, renal morphological alterations, and mRNA expression levels of phosphoenolpyruvate carboxykinase (PEPCK) and glucose transporter 2 (GLUT2) among the control group, the FK506 group and the FK506 + GW4064 (a FXR agonist) group (n = 7) were measured. The intracellular location of peroxisome proliferator activated receptor γ coactivator-1α (PGC1α) and forkhead box O1 (FOXO1) was detected by immunofluorescence. Human renal cortex proximal tubule epithelial cells (HK-2) were treated with 15 μM FK506 or 4 μM FXR agonist (GW4064) for 24, 48 and 72 h, and the expression levels of FXR, gluconeogenesis and glucose uptake, representing the enzymes PEPCK and GLUT2, were detected with real-time PCR and western blot analyses. Finally, the mRNA levels of PEPCK and GLUT2 in HK-2 cells were measured after FXR was upregulated.. FK506 significantly inhibited the mRNA and protein levels of FXR at 48 h and 72 h in HK-2 cells (P < 0.05). Meanwhile, FK506 promoted gluconeogenesis and inhibited glucose uptake in HK-2 cells (P < 0.05). However, overexpression of FXR in transfected HK-2 cell lines significantly inhibited gluconeogenesis and promoted glucose uptake (P < 0.05). The FXR agonist GW4064 significantly decreased the fasting blood glucose in mice challenged with FK506 for 3 months (P < 0.05), inhibited gluconeogenesis (P < 0.05) and significantly promoted glucose uptake (P < 0.05). Immunofluorescence staining and western blot analyses further revealed that FXR activation may affect the translocation of PGC1α and FOXO1 from the nucleus to the cytoplasm.. FXR activation may mitigate tacrolimus-induced diabetes mellitus by regulating gluconeogenesis as well as glucose uptake of renal cortex proximal tubule epithelial cells in a PGC1α/FOXO1-dependent manner, which may be a potential therapeutic strategy for the prevention and treatment of PTDM.

Topics: Animals; Cell Line; Diabetes Mellitus, Type 2; Fasting; Forkhead Box Protein O1; Gluconeogenesis; Glucose; Humans; Isoxazoles; Male; Mice, Inbred C57BL; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Receptors, Cytoplasmic and Nuclear; RNA, Messenger; Tacrolimus; Transplantation

The combination of AMD3100 and low-dose FK506 has been shown to accelerate wound healing in vivo. Although AMD3100 is known to work by releasing hematopoietic stem cells into circulation, the mechanism of FK506 in this setting has remained unknown. In this study, we investigated the activities of FK506 in human cells and a diabetic-rat wound model using a non-immunosuppressive FK506 analog named FKVP. While FKVP was incapable of inhibiting calcineurin, wound-healing enhancement with AMD3100 was unaffected. Further study showed that both FK506 and FKVP activate BMP signaling in multiple cell types through FKBP12 antagonism. Furthermore, selective inhibition of BMP signaling abolished stem cell recruitment and wound-healing enhancement by combination treatment. These results shed new light on the mechanism of action of FK506 in acceleration of wound healing, and raise the possibility that less toxic FKBP ligands such as FKVP can replace FK506 for the treatment of chronic wounds.

Topics: Animals; Benzylamines; Bone Morphogenetic Proteins; Cyclams; Diabetes Mellitus, Type 2; Disease Models, Animal; Drug Synergism; Female; Gene Knockout Techniques; Heterocyclic Compounds; Humans; Jurkat Cells; Ligands; Peptides, Cyclic; Phosphorylation; Rats; Receptors, CXCR4; Signal Transduction; Smad1 Protein; Smad5 Protein; Tacrolimus; Tacrolimus Binding Protein 1A; Wound Healing

This study aimed to evaluate the impact of 5 mg of prednisolone/day on HbA1c levels and its association with the development of pre-diabetes and new-onset diabetes mellitus (NODAT) in non-diabetic first renal transplant recipients on long-term follow-up.. Four hundred patients were analysed on an average of 4.1 ± 3.0 years after successful transplantation: 96 (24%) were steroid-free and 304 (76%) treated with 5 mg of prednisolone/day combined with cyclosporine A (CsA) or tacrolimus (Tac) as part of their immunosuppressive protocol. Pre-diabetes and NODAT were defined based on the HbA1c levels according to the current ADA guidelines. The Mann-Whitney U test and the Chi-square test were used to determine intergroup differences. Multivariate logistic regression analyses (adjusted for steroid-free versus 5 mg of prednisolone per day, body mass index (BMI), number of HLA mismatches, eGFR according to the CKD-EPI formula, sex, negative vs. positive PRA titre, CMV and HCV positivity of the recipient, CsA vs. Tac immunosuppressive medication, dialysis vintage (years), age at the last follow-up and time from transplantation to the last follow-up) were performed to identify an independent effect of low-dose steroids on the evolution of pre-diabetes and NODAT.. A small but statistically significant difference in HbA1c levels was observed between the control and the steroid groups (5.56 ± 0.54 vs. 5.67 ± 0.0.45%, p = 0.045). The incidence rates of pre-diabetes and NODAT per 100 patients per year were 9.3 and 3.0, respectively. Regression analysis showed that low-dose steroids (p = 0.026, risk ratio (RR) 1.789, 95%; confidence interval (CI) 1.007-3.040) and age (p = 0.000, RR 1.037/year, 95% CI 1.018-1.057) were associated with pre-diabetes, whereas BMI (p = 0.000, RR 1.190, 95% CI 1.084-1.307), age (p = 0.000, RR 1.087/year, 95% CI 1.047-1.129) and Tac use (p = 0.010, RR 3.300, 95% CI 1.328-8.196) were associated with NODAT.. Using 5 mg of prednisolone/day was associated with increased HbA1c levels and an increased risk in developing pre-diabetes, but not NODAT, whereas BMI, age and the use of tacrolimus were associated with an increased risk in developing NODAT.

Topics: Adult; Age Factors; Aged; Body Mass Index; Cyclosporine; Diabetes Mellitus, Type 2; Female; Glucocorticoids; Glycated Hemoglobin; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Male; Middle Aged; Prediabetic State; Prednisolone; Risk Factors; Tacrolimus; Time Factors; Transplant Recipients

β Cell transcription factors such as forkhead box protein O1 (FoxO1), v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA), pancreatic and duodenal homeobox 1, and neuronal differentiation 1, are dysfunctional in type 2 diabetes mellitus (T2DM). Posttransplant diabetes mellitus resembles T2DM and reflects interaction between pretransplant insulin resistance and immunosuppressants, mainly calcineurin inhibitors (CNIs). We evaluated the effect of tacrolimus (TAC), cyclosporine A (CsA), and metabolic stressors (glucose plus palmitate) on insulinoma β cells in vitro and in pancreata of obese and lean Zucker rats. Cells were cultured for 5 days with 100 μM palmitate and 22 mM glucose; CsA (250 ng/mL) or TAC (15 ng/mL) were added in the last 48 h. Glucose plus palmitate increased nuclear FoxO1 and decreased nuclear MafA. TAC in addition to glucose plus palmitate magnified these changes in nuclear factors, whereas CsA did not. In addition to glucose plus palmitate, both drugs reduced insulin content, and TAC also affected insulin secretion. TAC withdrawal or conversion to CsA restored these changes. Similar results were observed in pancreata of obese animals on CNIs. TAC and CsA, in addition to glucose plus palmitate, induced comparable inhibition of calcineurin and nuclear factor of activated T cells (NFAT); therefore, TAC potentiates glucolipotoxicity in β cells, possibly by sharing common pathways of β cell dysfunction. TAC-induced β cell dysfunction is potentially reversible. Inhibition of the calcineurin-NFAT pathway may contribute to the diabetogenic effect of CNIs but does not explain the stronger effect of TAC compared with CsA.

Topics: Animals; Calcineurin; Cyclosporine; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Glucose; Immunosuppressive Agents; Insulin; Insulin Resistance; Insulin-Secreting Cells; Nerve Tissue Proteins; NFATC Transcription Factors; Obesity; Rats; Rats, Zucker; Tacrolimus; Thinness

Post-transplant diabetes mellitus (PTDM) is a metabolic disorder occurring after solid organ transplantation during the therapy with calcineurin inhibitors. ATP-sensitive potassium channels KCNJ11 and KCNQ1 play an important role in the regulation of insulin secretion by β cells and development of diabetes mellitus. Numerous studies have confirmed the association between KCNJ11 and KCNQ1 gene polymorphisms and type 2 diabetes. The aim of this study was to examine the association between KCNJ11 and KCNQ1 gene polymorphisms and posttransplant diabetes mellitus in kidney allograft recipients treated with tacrolimus. The study included 201 patients who received kidney transplants. The patients were subdivided into two subgroups: patients with PTDM (N = 35) and patients without PTDM (N = 166). The association between KCNJ11 and KCNQ1 gene polymorphisms and post-transplant diabetes was studied in three models of univariate Cox regression analysis, i.e., additive, dominant and recessive. In these three models there were no statistically significant associations between KCNJ11 and KCNQ1 gene polymorphisms and PTDM. The results of this study suggest lack of association between KCNJ11 and KCNQ1 gene polymorphisms and post-transplant diabetes mellitus in kidney allograft recipients treated with tacrolimus in the Polish population.

Topics: Adult; Diabetes Mellitus, Type 2; Female; Humans; KCNQ1 Potassium Channel; Kidney Transplantation; Male; Middle Aged; Polymorphism, Genetic; Potassium Channels, Inwardly Rectifying; Tacrolimus

Trans-11 vaccenic acid (VA) is a fatty acid produced by ruminants entering the human food supply through meat and dairy products, which appears not to have the health risks associated with industrially produced trans-fatty acids. In this study, we investigated the effect of VA on insulin secretion in vivo in rats and in vitro in human and rat islets after diabetogenic insult.. Hyperglycemic clamp showed that VA dietary supplementation for 8 weeks significantly increased glucose turnover in rats with type 2 diabetes (T2D), accompanied by an elevated plasma C-peptide concentration, indicating improved insulin secretion. The β-cell area and proliferation rate were higher in T2D+VA than T2D group. Isolated islets from T2D+VA rats had higher glucose-stimulated insulin secretion (GSIS) than T2D group. In vitro, VA treatment for 24 and 48 h significantly enhanced GSIS in rat and human islets after diabetogenic challenges. The mRNA expression of G-protein-coupled receptor 40 (GPR40) and regenerating islet-derived 1α (REG-1α) were consistently increased by VA in both rat and human islets.. These results indicate that VA may improve insulin secretion and growth of islets in T2D, at least partly by altering GPR40 and REG-1α mRNA expression.

Topics: Aged; Animals; Cell Proliferation; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Dietary Supplements; Glucose; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Male; Middle Aged; Oleic Acids; Palmitic Acid; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Tacrolimus

New-onset diabetes mellitus after transplantation (NODAT) is a serious and frequent complication of solid organ transplantations. NODAT leads to 2-3 times higher cardiovascular morbidity and mortality. Visceral obesity is a key factor for diabetes mellitus type 2 and metabolic syndrome development, and is an independent risk factor for cardiovascular diseases.. The series consisted of 167 patients after primary kidney transplantation from a dead donor (64 patients had developed NODAT), average age of the series was 46.1±11.6 years. We retrospectively examined waist circumference, body mass index, and weight gain in the 12th month after transplantation. We examined average level of triglycerides, cholesterol, and immunosuppression throughout the 12 monitored months.. Patients with NODAT were significantly older (P=0.004) and had greater waist circumference (P<0.0001) and higher average sirolimus level (P=0.0262). We identified the following independent risk factors for NODAT by using multivariate analysis: age at the time of transplantation above 50 years (HR=2.5038, [95% CI: 1.7179 to 3.6492], P<0.0001), waist circumference in men greater than 94 cm (HR=1.9492, [95% CI: 1.1697 to 3.2480], P=0.0104) and in women greater than 80 cm (HR=4.5018, [95% CI: 1.8669 to 10.8553], P=0.009). By using correlation coefficient we have proved that greater waist circumference was related to higher incidence of NODAT (r=0.1935, [95% CI: 0.01156 to 0.3630], P=0.0374). Graft survival (death censored) 12 months after kidney transplantation was 97.1% in the control group and 95.3% in the NODAT group (P=0.5381). Patient survival 12 months after kidney transplantation in the control group was 98.1% and in the NODAT group it was 96.9% (P=0.6113).. We identified waist circumference as an independent risk factor for NODAT in our analysis.

Topics: Adult; Body Mass Index; Diabetes Mellitus, Type 2; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Renal Insufficiency, Chronic; Retrospective Studies; Risk Factors; Survival Rate; Tacrolimus; Waist Circumference

Diabetic nephropathy (DN) is the leading cause of end-stage renal failure, and podocyte injury plays a major role in the development of DN. In this study, we investigated whether tacrolimus (FK506), an immunosuppressor, can attenuate podocyte injury in a type 2 diabetic mellitus (T2DM) rat model with DN. Transmission electron microcopy was used to morphologically evaluate renal injury. The urinary albumin (UAL), creatinine clearance rate (Ccr) and major biochemical parameters, including glucose, insulin, serum creatinine (Scr), urea nitrogen, total cholesterol (CHO) and triglyceride (TG), were examined 12 weeks after the administration of FK506. The expressions of the canonical transient receptor potential 6 (TRPC6), nuclear factor of activated T-cells (NFAT) and nephrin were detected by Western blotting and qPCR. In the rat model of DN, the expressions of TRPC6 and NFAT were significantly elevated compared with the normal rat group; however, the treatment with FK506 normalized the increased expression of TRPC6 and NFAT and attenuated podocyte ultrastructure injury. UAL, Ccr and the biochemical parameters were also improved by the use of FK506. In cell experiments, FK506 improved the decreased expression of nephrin and suppressed the elevated expression of both TRPC6 and NFAT caused by high glucose in accordance with TRPC6 blocker U73122. Our results demonstrated that FK506 could ameliorate podocyte injury in T2DM, which may be related to suppressed expressions of TRPC6 and NFAT.

Topics: Albuminuria; Animals; Biomarkers; Blood Glucose; Blood Urea Nitrogen; Creatinine; Cytoprotection; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Down-Regulation; Immunosuppressive Agents; Male; Membrane Proteins; Microscopy, Electron, Transmission; NFATC Transcription Factors; Podocytes; Rats, Wistar; Tacrolimus; TRPC Cation Channels

Tacrolimus (Tac) is an immunosuppressive drug widely used to avoid organ rejection. New-onset diabetes after transplantation (NODAT) is a major complication among transplanted patients who receive Tac. The increased risk for NODAT could be partly mediated by the effect of Tac on mitochondria from pancreatic beta-cells. Common and rare mitochondrial DNA variants have been linked to the risk of diabetes. Our aim was to determine whether mtDNA polymorphisms/haplogroups were associated with NODAT in Tac-treated kidney transplanted.. Seven polymorphisms that define the common European haplogroups were determined in 115 NODAT and 197 no-NODAT patients.. Haplogroup H was significantly more frequent in the NODAT group (50% vs. 35%; p=0.01, OR=1.82). There was no difference between patients without and with (n=106) D2M prior to the transplant.. Mitochondrial haplogroup H was associated with the risk for NODAT among Tac-treated transplanted patients. The reported differences between the mtDNA variants could explain the increased NODAT-risk among H-patients.

Topics: Adolescent; Adult; Aged; Case-Control Studies; Diabetes Mellitus, Type 2; DNA, Mitochondrial; Female; Genetic Predisposition to Disease; Haplotypes; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Polymorphism, Genetic; Tacrolimus

Hyperglycemia is a common adverse event of immunosuppressive drugs used in organ transplant. Because cyclosporine is less diabetogenic than tacrolimus is, cyclosporine may be preferred in patients with pre-existing diabetes mellitus type 2, to prevent insulin treatment after a transplant.. From March 2005 to June 2011, adult renal transplant patients with pre-existing diabetes mellitus type 2, who were not treated with insulin before a transplant, were treated with cyclosporine in combination with mycophenolate mofetil and corticosteroids. For comparison, we used historical controls who were treated with tacrolimus instead of cyclosporine.. Of the 16 patients treated with cyclosporine, only 4 remained free of insulin treatment after a follow-up of least 1 year, compared with 2 of 12 patients who were treated with tacrolimus (25% vs 17%; P = .67). Almost all patients required insulin treatment within 2 months of the transplant, and patients required comparable doses of insulin at different times after the transplant in both groups. None of the baseline characteristics could sufficiently predict the need to start insulin treatment.. Cyclosporine cannot be preferred over tacrolimus to minimize either the chance of requiring insulin treatment posttransplant or the dosage of insulin in patients with pre-existing diabetes mellitus type 2.

Topics: Adrenal Cortex Hormones; Aged; Blood Glucose; Calcineurin Inhibitors; Case-Control Studies; Cyclosporine; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Humans; Hypoglycemic Agents; Immunosuppressive Agents; Insulin; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Tacrolimus; Time Factors; Treatment Outcome

Platelet hyperaggregability might contribute to vascular complications associated with type 2 diabetes mellitus (DM2).Experimental evidence supports a direct link between altered Ca(2+) entry and hyperaggregability in DM2 patients.. We aimed to investigate whether altered immunophilin expression and function are involved in the abnormal Ca(2+) entry observed in platelets from DM2 patients.. Inhibition of immunophilins by tacrolimus (FK506) and sirolimus (rapamycin) reduced Ca(2+) entry in platelets from healthy donors and DM2 patients. Similarly, immunophilin inhibitors reduced platelet degranulation in both healthy and DM2 subjects. Nevertheless, α-granule secretion reduction was greater than that observed for dense granules in platelets from DM2 patients. However, no difference was observed in the inhibition of secretion in platelets from healthy subjects. Additionally, altered expression of FK506 binding protein-52 (FKBP52) and coupling to Ca(2+) channels were found in platelets from DM2 patients compared to healthy subjects. Finally, reduction in platelet function from healthy subjects and DM2 patients in the presence of immunophilin antagonists was observed, being this dysfunction more evident in platelets from DM2 patients.. We suggest that, among others, FKBP52 expression and function are altered in platelets from DM2 patients, contributing to the altered Ca(2+) entry and hyperaggregability in these cells.

Topics: Blood Platelets; Calcium; Case-Control Studies; Diabetes Mellitus, Type 2; Humans; Immunophilins; Platelet Aggregation; Tacrolimus

To investigate the inhibition effects of pancreatic islet transplantation on the progression of obese type 2 diabetes, we analyzed the effects of surface camouflaged islet transplantation on delaying the disease progression in a db/db diabetic mouse model. Surface camouflaged islets using 6-arm-PEG-catechol were transplanted in db/db diabetic mice. The fat accumulation and toxicity in the liver, the expansion of islets in the pancreas, and the size change of abdominal adipocyte were analyzed. In addition, the blood glucose control, insulin levels and immunohistochemical staining of recovered tissues were analyzed after transplantation. Then co-administration of anti-CD154 monoclonal antibody and Tacrolimus (IT group) deterred the pathophysiological progression of obese type 2 diabetes. At day 3 of transplantation, the serum insulin concentration of IT group was increased compared to the db/db diabetic mice group. The immunohistochemical studies demonstrated that the mass of 6-arm-PEG-catechol grafted islet was preserved in the transplantation site for 14 days. Surface modification using 6-arm-PEG-catechol effectively inhibited the immune cell infiltration and activation of host immune cells when immunosuppressive drug was given to the db/db type 2 diabetes mice. Therefore, 6-arm-PEG-catechol grafted islets effectively restored the insulin secretion in islet recipients and prevented the disease progression in type 2 diabetes.

Topics: Adipocytes; Animals; Antibodies, Monoclonal; Blood Glucose; Catechols; CD40 Ligand; Cell Shape; Cell Size; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Disease Progression; Immunohistochemistry; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Islets of Langerhans Transplantation; Liver; Male; Mice; Mice, Inbred C57BL; Microscopy, Confocal; Polyethylene Glycols; Rats; Rats, Sprague-Dawley; Tacrolimus; Time Factors; Transplantation, Heterologous

New-onset diabetes after transplantation (NODAT) occurs commonly. Prior NODAT definitions have been inconsistent. Based on the American Diabetic Association criteria, we propose a new approach to defining NODAT.. Analysis of 1416 at-risk transplant recipients was performed. Data from three de novo Astellas registration transplant studies (two kidney and one liver) evaluated NODAT in 634 at-risk patients receiving tacrolimus, 630 at-risk patients receiving tacrolimus extended release, and 152 at-risk patients receiving cyclosporine. NODAT was defined as a composite endpoint consisting of first occurrence of one of four parameters: (i) two fasting plasma glucose levels ≥ 126 mg/dL (≥ 7.0 mmol/L) ≥ 30 days apart, (ii) oral hypoglycemic agent use for ≥ 30 consecutive days, (iii) insulin therapy for ≥ 30 consecutive days, and (iv) hemoglobin A1c ≥ 6.5%. We evaluated each of the above parameters, as well as the composite endpoint, in an attempt to establish an appropriate clinical approach to the diagnosis of NODAT.. The composite definition results in a 1-year NODAT incidence of 30% to 37% in kidney and 44% to 45% in liver transplant recipients treated with tacrolimus. NODAT incidence was significantly higher with tacrolimus than cyclosporine; there was no difference between the two tacrolimus formulations.. Based on these analyses, the proposed composite definition for NODAT, incorporating broader criteria, is recommended for clinical trials. Appropriate definitions of NODAT allow for a better understanding of the incidence of this complication and may result in earlier initiation of therapy with improved long-term outcomes.

Topics: Clinical Trials as Topic; Cyclosporine; Diabetes Mellitus, Type 2; Female; Graft Survival; Humans; Hypoglycemic Agents; Immunosuppressive Agents; Incidence; Kidney Transplantation; Liver Transplantation; Male; Middle Aged; Multivariate Analysis; Postoperative Complications; Prevalence; Registries; Risk Factors; Tacrolimus; Terminology as Topic

Topics: Adrenal Cortex Hormones; Adult; Aged; Anti-Bacterial Agents; Breast Diseases; Colchicine; Diabetes Mellitus, Type 2; Drug Resistance; Female; Granuloma; Humans; Hypertension; Immunosuppressive Agents; Isotretinoin; Male; Pyoderma Gangrenosum; Remission Induction; Tacrolimus

The purpose of the present study was to evaluate the difference in BMI pattern between patients with persistent new-onset diabetes after transplantation (P-NODAT) and without new-onset diabetes after transplantation (N-NODAT) in a retrospective matched case-control (1:3) analysis. Thirty-six patients who developed P-NODAT were identified among 186 adult renal transplant recipients with no evidence of pretransplant diabetes mellitus who underwent kidney transplantation from September 1997 to March 2008 and were treated with a triple regimen including tacrolimus. The controls were selected to match the patients for pretransplant BMI, age at transplantation (± 5 yr), and date of transplantation (± 12 months). Finally, 20 P-NODAT patients and 60 N-NODAT patients were selected. The pre- and posttransplant BMI data were collected every 16 weeks for up to 80 weeks. The clinical characteristics did not differ between the P-NODAT group and N-NODAT group. BMI increased faster in the P-NODAT group than in the N-NODAT group. The mixed-model analysis showed that patients with P-NODAT exhibited a faster increase in BMI. P-NODAT is associated with posttransplant weight gain. The risk of P-NODAT should be considered in patients with rapid weight gain after transplantation.

Topics: Adult; Body Mass Index; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Retrospective Studies; Tacrolimus; Time Factors; Weight Gain

Calcineurin inhibitors (CNIs) revolutionized the field of organ transplantation and remain the standard of care 40 years after the discovery of cyclosporine. The early impressive results of cyclosporine in kidney transplant recipients led to its subsequent use in other organ transplant recipients and for treatment of a variety of autoimmune diseases as well. In this review, we examine the discovery of CNIs, their mechanism of action, preclinical and clinical studies with CNIs, and the usage of CNIs in nontransplant recipients. We review the mechanisms of renal toxicity associated with CNIs and the recent efforts to avoid or reduce usage of these drugs. Although minimization strategies are possible, safe, and of potential long-term benefit, complete avoidance of CNIs has proven to be more challenging than initially thought.

Topics: Animals; Autoimmune Diseases; Calcineurin; Calcineurin Inhibitors; Clinical Trials as Topic; Cyclosporine; Diabetes Mellitus, Type 2; Drug Evaluation, Preclinical; Drug Therapy, Combination; Forecasting; Graft Rejection; History, 20th Century; History, 21st Century; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Lymphocyte Activation; Meta-Analysis as Topic; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; T-Lymphocytes; Tacrolimus

Incidents of new-onset vitiligo attributed to infliximab therapy for rheumatoid arthritis and ulcerative colitis have been reported. Reported cases share a common theme in that symptoms manifested in close proximity to the initiation or significant dose increase of the medication. This case describes the presentation of infliximab-induced vitiligo in a patient using it for long-term treatment of stable pityriasis rubra pilaris. The patient was initiated and titrated to a stable dose of infliximab totaling 27 months' duration. He was able to achieve near-complete resolution of symptoms before developing depigmented patches consistent with vitiligo. Infliximab was discontinued. Tacrolimus 0.1% ointment and narrow-band ultraviolet B light successfully repigmented the patches. The association of discontinuing infliximab and resolution of vitiligo suggests infliximab had a role in this case. Though the mechanism of involvement is undetermined, infliximab may have induced an autoimmune process by paradoxically activating lymphocytes. Alternatively, infliximab antibodies may have led to the process by disrupting the normal balance of cytokines.

Topics: Antibodies, Monoclonal; Antirheumatic Agents; Arthritis, Rheumatoid; Diabetes Mellitus, Type 2; Gout; Humans; Immunosuppressive Agents; Infliximab; Male; Middle Aged; Pityriasis Rubra Pilaris; Tacrolimus; Ultraviolet Therapy; Vitiligo

A 50-year-old female patient, who had had a long-term history of myelodysplastic syndrome and type II diabetes mellitus, had developed acute myelogenous leukemia and received allogeneic bone marrow transplantation (BMT). She was being treated with tacrolimus, methotrexate and prednisolone for prophylaxis and treatment of graft-versus-host disease, and with intensive insulin therapy for better glycemic control. The patient suddenly developed marked leg edema at 27 days after starting intensive insulin therapy (on day 40 after BMT) without coexistence or exacerbation of apparent causes such as renal failure, cardiac dysfunction or leg thrombosis around the onset of leg edema. Interestingly, the leg edema regressed soon after daytime hyperglycemia and intensive insulin therapy were performed. Histopathological examination revealed slight dermal edema and small bullae with little inflammatory infiltration but no signs of autoimmune blistering diseases or vasculitis. These findings indicate that the present case may be considered a form of so-called insulin edema occurring during intensive insulin therapy after BMT.

Topics: Bone Marrow Transplantation; Diabetes Mellitus, Type 2; Edema; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Insulin; Leg; Methotrexate; Middle Aged; Myelodysplastic Syndromes; Prednisolone; Skin Diseases; Tacrolimus; Treatment Outcome

KCNJ11 polymorphisms have been linked to the risk of developing type 2 diabetes. Our aim was to define the contribution of KCNJ11 to new-onset diabetes after transplantation (NODAT) among patients treated with Tacrolimus (Tac). A total of 115 NODAT and 205 non-NODAT were genotyped for rs5219 (p.E23K). AA+AG genotypes were significantly associated with NODAT-risk (p=0.004; OR=2.10). The reported effect of this KCNJ11 polymorphism on insulin release by beta cells could explain this association.

Topics: Adolescent; Adult; Aged; Calcineurin Inhibitors; Diabetes Mellitus, Type 2; Female; Genotype; Heart Transplantation; Humans; Immunosuppressive Agents; Insulin; Insulin Secretion; Insulin-Secreting Cells; Kidney Transplantation; Male; Middle Aged; Polymorphism, Single Nucleotide; Potassium Channels, Inwardly Rectifying; Tacrolimus; Young Adult

To evaluate the efficacy and safety of conversion from calcineurin inhibitors to sirolimus among liver transplant recipients with calcineurin inhibitor-induced complications.. After receiving liver transplants, 25 patients with calcineurin inhibitor-induced complications (22 renal dysfunction and 3 new-onset diabetes mellitus) were converted from sirolimus to tacrolimus. The serum creatinine, sirolimus trough level, liver function, acute rejection episodes, and drug-related adverse effects were monitored.. The patients were followed for 12 to 50 months (median, 25 months). The renal function of the 22 patients with renal dysfunction improved after sirolimus conversion. The serum creatinine levels were significantly lower at 3 months after conversion versus before conversion (113.2 ± 21.8 μmol/L vs 163.2 ± 45.3 μmol/L; P < .05). At the end of the follow-up, the average serum creatinine level was 101.9 ± 23.4 μmol/L among the 20 living recipients. Diabetes also was under control in 3 diabetic recipients after the conversion. Four patients experienced episodes of acute rejection, and intravenous steroid bolus therapy was administered in 2 of them. No graft was lost because of acute rejection. The adverse effects of sirolimus included hyperlipidemia (7/25), anemia (8/25), and mouth ulcers (9/25). All these adverse effects were relieved after a short-term symptomatic therapy, and no patient was withdrawn from the conversion trial.. Sirolimus monotherapy is effective and safe in liver transplant recipients. Conversion to sirolimus was associated with a sustained improvement in renal function and diabetes mellitus without an increased incidence of acute rejection episodes.

Topics: Acute Disease; Anemia; Calcineurin Inhibitors; Creatinine; Diabetes Mellitus, Type 2; Follow-Up Studies; Graft Rejection; Humans; Hyperlipidemias; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Oral Ulcer; Retrospective Studies; Sirolimus; Tacrolimus

New-onset diabetes after transplantation (NODAT) is a major complication after kidney transplantation. The risk factors for NODAT include the use of calcineurin inhibitors as part of the immunosuppressive regimen, among which tacrolimus has the most pronounced diabetogenic effect. Both NODAT and type 2 diabetes mellitus (T2DM) share several risk factors. Recent studies have identified a number of common genetic variants associated with increased risk of T2DM. Here we report the results of our study on the potential effect of single nucleotide polymorphisms (SNPs) previously associated with T2DM on the risk of NODAT in kidney transplant patients medicated with tacrolimus.. Seven SNPs in six genes known to increase the risk of T2DM in Caucasians were genotyped by means of TaqMan assays in 235 kidney transplant patients medicated with tacrolimus: rs4402960 and rs1470579 in IGF2BP2; rs1111875 in HHEX; rs10811661 upstream of CDKN2A/B; rs13266634 in SLC30A8; rs1801282 in PPARG; rs5215 in KCNJ11. The TCF7L2 rs7903146 SNP was also included in the multivariate analysis.. None of the analyzed SNPs was significantly associated with the risk of NODAT. However, the IGF2BP2 rs4402960 T allele was present significantly more frequently among patients diagnosed with NODAT more than 2 weeks after transplantation (p = 0.048). Mean (± standard deviation) number of the analyzed alleles tended to be lower in patients without NODAT (6.19 ± 1.71) than in NODAT patients (6.58 ± 1.1.95; p = 0.09) and significantly lower compared to late-onset NODAT patients (7.03 ± 1.88; p = 0.018). Multivariate analysis confirmed the significance of 'diabetogenic' allele number in late-onset NODAT development [odds ratio (OR) 1.37, 95 % confidence interval (CI) 1.05-1.78; p = 0.017]. Additionally, individuals carrying >7 of the analyzed 'diabetogenic' alleles were at a significantly higher risk of NODAT (OR 2.17, 95 % CI 1.18-3.99; p = 0.015).. Complex analysis of genotypes increasing the risk of diabetes may lead to the identification of NODAT susceptibility predictors.

Topics: Adult; Diabetes Mellitus, Type 2; Female; Genetic Predisposition to Disease; Genotype; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Polymorphism, Single Nucleotide; Risk Factors; Tacrolimus

We sought to study the prevalence, risk factors, and long-term prognosis of posttransplant diabetes mellitus.. We studied all patients with end-stage renal disease without diabetic nephropathy who received a kidney transplant and were followed-up at our center since 1983 (n=218; age, 44.3 ± 13.1 y). Patients with new-onset diabetes after transplant were compared to kidney transplant recipients without risk factors for diabetes mellitus. Patients with new-onset diabetes after transplant were divided into subgroups according to time of onset (early; < 90 d vs late, ≥ 90 d).. In total, 73/218 patients (33%) developed new-onset diabetes after transplant. Patients with new-onset diabetes after transplant were significantly older (51.2 ± 11.4 vs 40.7 ± 12.5 y; P < .001) and had a tendency to have a higher body mass index (29.6 ± 8.7 vs 21.6 ± 7.8 kg/m2; P =.05) than those that did not have new-onset diabetes after transplant. In multivariate analysis, age (P < .001), hepatitis C virus infection (P < .05), family history of diabetes mellitus (P < .03), and tacrolimus use (P < .001) were independent risk factors. Five- and 10-year death censored patient survival rates were worse in those that had new-onset diabetes after transplant compared with controls (log rank, 0.04), whereas there was no difference in outcomes between the early and late subgroups.. The prevalence of new-onset diabetes after transplant was 33%. Age, body weight at time of transplant, tacrolimus use, family history of diabetes mellitus, and hepatitis C virus infection are independent risk factors for new-onset diabetes after transplant. New-onset diabetes after transplant has a negative effect on patient survival, irrespective of the time of onset and duration of diabetes.

Topics: Adult; Age Distribution; Body Mass Index; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Hepatitis C; Humans; Immunosuppressive Agents; Incidence; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Multivariate Analysis; Postoperative Complications; Prevalence; Prognosis; Retrospective Studies; Risk Factors; Tacrolimus; Treatment Outcome

New onset posttransplant diabetes mellitus (PTDM) has a high incidence after kidney transplantation in patients medicated with tacrolimus. PTDM can adversely affect patient and graft survival. The pathophysiology of PTDM closely mimics type 2 diabetes mellitus (T2DM). One of the possible genetic factors predisposing individuals to PTDM might be a polymorphism in the transcription factor 7-like 2 gene (TCF7L2). This polymorphism has previously been associated with increased risk of T2DM in the general population. Therefore, the present study aimed to evaluate TCF7L2 polymorphisms in PTDM in kidney transplant patients medicated with tacrolimus. Non-diabetic kidney transplant patients medicated with tacrolimus (n = 234) were genotyped for the presence of TCF7L2 gene variants (rs12255372 and rs7903146) using TaqMan probes. Of the 234 patients, 66 patients had developed PTDM and 168 had not. Frequencies of the studied single nucleotide polymorphisms (SNPs) did not differ significantly between the study groups. Moreover, haplotype analyses failed to detect any associations between TCF7L2 haplotypes and PTDM. However, in late-onset PTDM (developed later that 2 weeks from transplantation), frequencies of the rs7903146 TT genotype and T minor allele were significantly increased compared to non-PTDM controls (17.9% vs. 5.9%, p = 0.017, OR: 4.13, 95% CI: 1.19-14.33 for TT genotype, 39.3% vs. 25.9%, p = 0.038 for T allele). If the application of TCF7L2 rs7903146 SNPs as a marker for PTDM is confirmed by further independent studies, replacing tacrolimus with other immunosuppressants could be warranted in patients at high risk of PTDM, as diagnosed by TCF7L2 genotyping.

Topics: Adult; Diabetes Mellitus, Type 2; Female; Genotype; Haplotypes; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Tacrolimus; Transcription Factor 7-Like 2 Protein

Endoplasmic reticulum stress has been implicated in the pathogenesis of new-onset diabetes after transplantation (NODAT) and of metabolic disorders. Activated Transcription Factor 6 (ATF6), which is activated during endoplasmic reticulum stress, is involved in lipogenesis and gluconeogenesis. Tacrolimus may induce endoplasmic reticulum stress in pancreatic beta cells. Since studies have demonstrated that single nucleotide polymorphisms (SNPs) of ATF6 are associated with type 2 diabetes, we sought to determine whether their mutations were associated with NODAT among renal transplant recipients treated with tacrolimus.. We genotyped 269 renal transplant recipients using TaqMan assays for allelic discrimination for 6 ATF6 gene polymorphisms: rs10918215, rs7514053, rs1058405, rs4479731, rs2340721, and rs13401. All patients received an immunosuppressive regimen including tacrolimus. We analyzed all previously known risk factors for NODAT.. We could not confirm are association between ATF6 SNP and NODAT. We observed a significant association between ATF6 SNP rs2340721 and increased body weight and body mass index (BMI) both upon univariate and multivariate analyses. The average BMI was higher among patients with 2 mutant SNP2 (rs2340721) alleles (CC) than those with 2 wild-type alleles (AA): 23.8 ± 3.7 versus 25.5 ± 4.4 kg/m2 (P = .02). The odds ratio (95% confidence interval [CI]) for BMI associated with the CC genotype was 2.43 (1.16-5.09; P = .02).. ATF6 polymorphisms were not associated with NODAT among our population of renal transplant recipients treated with tacrolimus. However, these data underscore the role of ATF6 and endoplasmic reticulum stress in the regulation of metabolic flux among patients treated with tacrolimus, suggesting that inherited disturbances of endoplasmic reticulum stress signaling could predispose people to obesity.

Topics: Activating Transcription Factor 6; Adult; Alleles; Body Mass Index; Diabetes Mellitus, Type 2; Endoplasmic Reticulum; Female; Genotype; Gluconeogenesis; Heterozygote; Humans; Immunosuppressive Agents; Kidney Transplantation; Lipogenesis; Male; Middle Aged; Multivariate Analysis; Mutation; Polymorphism, Genetic; Prospective Studies; Risk Factors; Tacrolimus

The aim of this paper was to report the case of type 2 diabetes and significant insulin resistance that improved dramatically after removal of a pheochromocytoma in a liver transplant recipient , and to provide a review of the relevant literature. We describe the clinical presentation, diagnostic results and management of the patient. In addition, we performed a PubMed search for related English language articles, to provide an overview of the pertinent literature. A 53 year old woman with a history of an orthotopic liver transplantation and insulin-requiring type 2 diabetes was admitted to the hospital with fever, diaphoresis, tachycardia and hypertension. A pheochromocytoma was diagnosed and removed. The patient subsequently developed hypoglycemia and required no further insulin therapy. Pheochromocytomas have been described to lead to hyperglycemia and diabetes, due to the suppression of insulin release and increased insulin resistance. Furthermore, a review of the literature revealed only 3 other reported cases of pheochromocytomas in organ transplant recipients. None of these pheochromocytomas were believed to have occurred de novo after transplantation. This is the first report of a pheochromocytoma in a liver transplant recipient and possibly the first case of a de novo pheochromocytoma in any organ transplant recipient. Moreover, this case showcases pheochromocytomas as a rare cause of diabetes mellitus.

Topics: Adrenal Gland Neoplasms; Adrenalectomy; Diabetes Mellitus, Type 2; Female; Glipizide; Glucocorticoids; Humans; Hypertension; Hypoglycemic Agents; Immunosuppressive Agents; Insulin; Insulin Resistance; Insulin Secretion; Liver Diseases, Alcoholic; Liver Transplantation; Middle Aged; Pheochromocytoma; Postoperative Complications; Remission Induction; Tachycardia; Tacrolimus

New-onset, posttransplant diabetes mellitus (PTDM) has a high incidence after kidney transplantation in patients medicated with tacrolimus, and may adversely affect the patient and graft survival. The pathophysiology of PTDM closely mimics that of type II diabetes mellitus (T2DM). One of possible genetic factors predisposing to PTDM might be polymorphism in calpain-10 gene (CAPN10), previously associated with increased risk of T2DM in general population. Therefore, the present study was aimed at evaluation of CAPN10 gene polymorphisms in PTDM in kidney transplant patients medicated with tacrolimus. A total of 214 nondiabetic kidney transplant patients medicated with tacrolimus (56 patients with PTDM and 158 patients without PTDM were genotyped for the presence of CAPN10 gene variants (SNP-43: rs3792267:G>A, SNP-19: rs3842570 ins/del and SNP-63: rs5030952:C>T) using PCR-based assays. Frequency of SNP-63 minor allele was slightly increased in PTDM patients (P=0.056), and an association of SNP-63 heterozygosity and the risk of PTDM (odds ratios (OR)=2.45, P=0.023) was observed. An increased odds for PTDM development in patients carrying 1-1-2 haplotype (rs3792267:G-rs3842570:ins-rs5030952:T) compared to noncarriers was also noted (OR=2.35, P=0.026). Patients' higher body mass index and SNP-63 minor T allele carrier status were identified as independent PTDM risk factors, confirmed by multivariate regression analysis. This is the first study of CAPN10 polymorphism in relation to PTDM risk. However, the application of SNP-63 (rs5030952:C>T) as a marker of PTDM should be verified by further independent studies.

Topics: Adult; Body Mass Index; Calpain; Diabetes Mellitus, Type 2; Female; Humans; Kidney Transplantation; Male; Middle Aged; Polymorphism, Single Nucleotide; Risk Factors; Tacrolimus

The diabetic heart is resistant to ischemic preconditioning because of diabetes-associated impairment of phosphatidylinositol 3-kinase (PI3K)-Akt signaling. The mechanism by which PI3K-Akt signaling is impaired by diabetes remains unclear.. Here, we examined the hypothesis that phosphorylation of Jak2 upstream of PI3K is impaired in diabetic hearts by an angiotensin II type 1 (AT1) receptor-mediated mechanism.. Infarct size (as percentage of risk area) after 20-minute ischemia/2-hour reperfusion was larger in a rat model of type 2 diabetes (Otsuka-Long-Evans-Tokushima fatty [OLETF] rat) than in its control (Long-Evans-Tokushima-Otsuka [LETO] rat) (60.4+/-1.6% versus 48.4+/-1.3%). Activation of Jak2-mediated signaling by erythropoietin or DADLE ([D-Ala2, D-Leu5]-enkephalin acetate), a delta-opioid receptor agonist, limited infarct size in LETO rats (27.7+/-3.4% and 24.8+/-5.0%) but not in OLETF rats (53.9+/-5.3% and 55.0+/-2.2%). Blockade of the AT1 receptor by valsartan or losartan for 2 weeks restored the myocardial response of OLETF rats to erythropoietin-induced infarct size limitation (39.4+/-4.9% and 31.2+/-7.5). In OLETF rats, erythropoietin failed to phosphorylate both Jak2 and Akt, and calcineurin activity was significantly higher than in LETO rats. Two-week treatment with valsartan normalized calcineurin activity in OLETF rats and restored the response of Jak2 to erythropoietin. This effect of AT1 receptor blockade was mimicked by inhibition of calcineurin by FK506.. These results suggest that the diabetic heart is refractory to protection by Jak2-activating ligands because of AT1 receptor-mediated upregulation of calcineurin activity.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Calcineurin; Diabetes Mellitus, Type 2; Enkephalin, Leucine-2-Alanine; Erythropoietin; Immunosuppressive Agents; Ischemic Preconditioning, Myocardial; Janus Kinase 2; Losartan; Male; Myocardial Reperfusion Injury; Myocardium; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Rats, Inbred OLETF; Receptor, Angiotensin, Type 1; Receptors, Opioid, delta; Signal Transduction; Species Specificity; Tacrolimus; Tetrazoles; Up-Regulation; Valine; Valsartan

The calcineurin inhibitors-cyclosporine and tacrolimus-are the mainstay of immunosuppressive therapy in solid organ transplantation. These drugs produce severe adverse drug effects (ADEs) such as nephrotoxicity, posttransplantation diabetes mellitus, and hypertension. Accumulated evidence suggests that the development of type 2 diabetes, hypertension, and renal failure may be associated with specific DNA genotypes. In this review, the genes involved with the development of these disease processes are compared with those implicated in calcineurin inhibitor-induced ADEs. The renin-angiotensin system genes, cytokine-encoding genes, and plasminogen activator inhibitor type 1 genes have been implicated in calcineurin inhibitor-induced nephrotoxicity, as well as in development of renal failure. A number of genes are implicated in contributing to diabetes, and these include the vitamin D receptor gene, VDR; hepatocyte nuclear factor genes, HNF; transcription factor 7-like 2 gene, TCF7L2; angiotensin-converting enzyme gene, ACE; cytokines; peroxisome proliferator-activated receptor gamma gene, PPARG; and others. Studies have suggested that the VDR, PPARG, HNF1A, and adenosine 5'-triphosphate-binding cassette ABCC8 (which encodes the sulfonylurea receptor) genes are associated with calcineurin inhibitor-induced diabetes. The genes encoding for the angiotensin-converting enzyme, endothelial constitutive nitric oxide synthase, and cytochrome P450 3A isoenzyme have been involved in the development of hypertension and in calcineurin inhibitor-induced hypertension. The genetic study of disease states can be the stepping stones for thoroughly understanding the genetic basis of ADEs. Gene polymorphisms are implicated in the development of diseases and corresponding disease-like ADEs. The disease-associated genes provide candidate genes for exploring ADEs and may provide genomic biomarkers for assessing the risk for developing severe calcineurin inhibitor-related ADEs as well as for developing preventive strategies.

Topics: Biomarkers, Pharmacological; Calcineurin Inhibitors; Cyclosporine; Diabetes Mellitus, Type 2; Drug Discovery; Genotype; Humans; Hypertension; Immunosuppressive Agents; Polymorphism, Genetic; Precision Medicine; Renal Insufficiency; Risk Factors; Tacrolimus

Several groups identified pre-transplant factors which contribute to the development of new onset of diabetes after transplantation (NODAT).. To identify post-transplant risk factors for NODAT.. 55 stable renal transplant patients were divided into group A of 34 recipients with normoglycemia and group B of 21 recipients with impaired fasting glucose. Markers including insulin, pro-insulin, soluble receptors for advanced glycated end products (sRAGE), adiponectin, malondialdehyde, homeostasis model assessment of insulin resistance (HOMA-IR), and beta-cell function were calculated at the outset and correlated, thereafter, with the later development of NODAT after a follow-up duration of 14.98 +/- 3.97 months.. 11.8 and 19% of groups A and B respectively developed NODAT. Insulin, sRAGE, HOMA-IR and basal fasting plasma glucose correlated with the development of NODAT in univariate analysis. A baseline insulin level of 54.54 mU/l predicted the development of NODAT with a specificity of 95.45% and was the only significant factor in the multivariate analysis. beta-Cell function was not different among the three groups.. A long prodrome of insulin resistance (IR) exists prior to development of NODAT. 50% of patients with NODAT will remit to a normoglycemic state. IR, rather than beta-cell dysfunction, precedes the development of NODAT. Serum insulin in stable non-diabetic renal transplant patients can be used as a confirmatory test to the development of future NODAT.

Topics: Adult; Blood Glucose; Case-Control Studies; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Humans; Immunosuppressive Agents; Insulin; Insulin Resistance; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Predictive Value of Tests; Prospective Studies; Risk Factors; Sensitivity and Specificity; Tacrolimus

Topics: Adolescent; Diabetes Mellitus, Type 2; Humans; Immunosuppressive Agents; Male; Postoperative Complications; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Stem Cell Transplantation; Tacrolimus

The effect of diabetes mellitus on the pharmacokinetics of tacrolimus is not well characterized. We have compared tacrolimus 12-hour steady-state concentration-time profiles in diabetic (n = 11) and demographically matched nondiabetic (n = 9) stable kidney transplant recipients and derived a limited sampling strategy for the estimation of tacrolimus area under the concentration-time curve (AUC(0-12)). Tacrolimus concentration was measured by liquid chromatography tandem mass spectrometry and acetaminophen absorption method was used to characterize gastric emptying time. Demographic and biochemical characteristics were comparable between the two groups with the exception of significantly higher glycated hemoglobin levels in patients with diabetes (P = 0.02). Time to maximum concentration (T(max)) of acetaminophen was significantly longer in diabetics [D: 74.1 minute versus nondiabetics (ND): 29.3 minutes, P = 0.02]; however, tacrolimus T(max) was not significantly different (D: 121 minutes versus ND: 87 minutes, P = 0.15). Median (interquartile range) of tacrolimus AUC(0-12) was 114 (101-161) microg*hr/L in patients with diabetes and 113 (87-189) microg*hr/L in nondiabetics (P = 0.62). The following limited sampling equation [AUC(pred) (microg*hr/L) = 18.70 - 1.72 C(1 hr) - 4.09 C(2 hr) + 14.40 C(3 hr)] was derived from a training data set that included 10 patients. The correlation coefficient between model-predicted and observed AUC0-12 values was 0.999. Mean prediction error and root mean square error of the model-predicted values derived from the patients in validation data set were 0.04 and 17.48 microg*hr/L, respectively. In conclusion, it appears that diabetes has a modest effect on the rate but not the extent of tacrolimus absorption, and a three-point abbreviated sampling strategy common to both groups may prove useful for the estimation of tacrolimus exposure in kidney transplant recipients.

Topics: Adolescent; Adult; Aged; Area Under Curve; Chromatography, Liquid; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug Monitoring; Gastric Emptying; Humans; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Models, Biological; Regression Analysis; Sampling Studies; Tacrolimus; Tandem Mass Spectrometry

Adverse effects associated with calcineurin inhibitors may impact their clinical utility in some patients. This study characterizes the clinical outcomes of liver transplanted (LT) patients who experienced diabetes mellitus (DM) on tacrolimus-based regimen and were converted to cyclosporine-based therapy. Since January 2002, all patients with DM on a tacrolimus-based regimen were recruited and converted to cyclosporine-based therapy, after a 6-month minimal follow-up after LT. Clinical and laboratory data related to the clinical course of the patients were recorded. Twenty-five patients were included after a median delay of 54 months after LT [seven women and 18 men, 51 years (range 30-69)]. There were 11 patients with insulin-treated DM (ITDM), 14 patients with noninsulin-treated DM (NITDM), and the glycemic control was poor (HbA1c > 6.5%) in 13/25 patients (52%). After a median follow-up of 20 months after conversion, there were four patients with ITDM, 17 patients with NITDM, and four patients without DM, and the glycemic control was poor in 3/25 patients (12%). Four patients returned to tacrolimus because of arterial hypertension or digestive side-effects. In conclusion, our results suggest that conversion from tacrolimus to cyclosporine in stable LT patients with DM is well tolerated and beneficial on glycemic control.

Topics: Adult; Aged; Blood Glucose; Cyclosporine; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Humans; Immunosuppression Therapy; Liver Transplantation; Male; Middle Aged; Retrospective Studies; Tacrolimus; Treatment Outcome

Post-transplant diabetes mellitus (PTDM) and impaired glucose tolerance are now considered among the major adverse events following organ transplantation. The present study was aimed at investigating the regulation of glucose metabolism in pediatric recipients of a kidney transplant (KT), receiving tacrolimus or cyclosporine A-based immunosuppression. Twelve subjects, eight males and four females, aged 12.1+/-3.8 yr, and with a mean time from KT of 45.6 months were enrolled in the study. All patients had a basal evaluation of fasting glucose (GF), fasting insulin (IF), C-peptide and glycated hemoglobin (HbA1c) levels. They then underwent oral glucose tolerance test (OGTT), with measurement of blood glucose and insulin concentration. Two children had impaired GF, associated with supernormal HbA1c levels, one patient showed impaired glucose tolerance, none had PTDM. Peripheral insulin resistance, as measured by quantitative insulin sensitivity check index (QUICKI) and homeostasis model assessment estimate of insulin sensitivity (HOMA-IR) index, was enhanced in 3 patients. Subsequently, GF significantly increased with time from transplant (p=0.01), while fasting C-peptide and the area under the curve of insulin correlated with creatinine clearance. In conclusion, our results, although generated in a small sample size, would suggest that long-term follow-up of children receiving a KT should extend to explore the response to oral glucose load and at least the basal measure of insulin response.

Topics: Adolescent; Blood Glucose; Body Mass Index; Child; Cohort Studies; Cyclosporine; Diabetes Mellitus, Type 2; Female; Glucose; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Immunosuppressive Agents; Insulin; Kidney Transplantation; Male; Tacrolimus

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Mass Screening; Patient Selection; Perioperative Care; Risk Assessment; Risk Factors; Risk Reduction Behavior; Tacrolimus; United States

To determine the prevalence of diabetes and its glycemic control in the renal transplant population of northeast England (Newcastle, Sunderland, Middlesborough, and Carlisle).. All renal transplant notes in northeast England were reviewed. Data on patient details, type of diabetes, time of onset of diabetes, diabetes medications, time of insulin commencement, date of renal transplant, immunosuppressive medications, and HbA(1C) were recorded.. Living renal transplant patients (n = 1073) transplanted between March 1982 and November 5, 2003 were identified. One hundred and nine (10.2%) patients had diabetes, of whom 39 were type 1 and 70 were type 2. Median HBA(1C) in patients with type 1 diabetes on tacrolimus was 10.1% +/- 1.94% (SD) versus 7.8% +/- 1.98% (SD) for patients not on tacrolimus. Among patients with type 2 diabetes, 25 had diabetes prior to transplant and 45 (4.5%) developed posttransplant diabetes (PTDM). Those who developed PTDM and were taking tacrolimus were more likely to require insulin for blood glucose control (0.39 U/kg/24 hours vs 0 U/kg/24 hours; P = .05) compared to those not on tacrolimus. Both type 1 and type 2 diabetics on tacrolimus showed better preservation of renal function as measured by mean serum creatinine (type 1: 145 +/- 53 vs 196 +/- 74, P = .02; type 2 pretransplant: 159 +/- 73 vs 172 +/- 59, P = .35; type 2 posttransplant: 123 +/- 35 vs 167 +/- 63, P = .01).. Tacrolimus use in renal transplant patients with diabetes appeared to be associated with more problematic blood glucose control; however, it seemed to be better at preserving renal function. Intensive blood glucose monitoring is recommended for this group.

Topics: Blood Glucose; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; England; Glycated Hemoglobin; Humans; Immunosuppressive Agents; Kidney Transplantation; Medical Audit; Retrospective Studies; Tacrolimus

The new onset of posttransplant diabetes mellitus (PTDM) is a common problem after solid organ transplantation. Because insulin resistance plays a significant role in the development of PTDM, we treated 40 consecutive patients with PTDM after liver and kidney transplantation with the insulin sensitizer rosiglitazone (ROSI).. Thirty-three of 40 patients with PTDM were initially stabilized with twice-daily NPH and regular insulin. All patients subsequently began ROSI 4 mg per day. Patients were followed for a mean of 26 weeks and insulin was adjusted using home blood glucose data and hemoglobin A1C (HBA1C).. During 12 months of study, 32/107 liver transplant patients (30%) and 8/205 kidney transplant patients (4%) patients developed PTDM. After 3-4 months of insulin and ROSI therapy, insulin was able to be discontinued in 30/33 (91%) patients with PTDM. In all, 12/40 (30%) patients maintained normal HBA1C levels (5.6+/-0.8%) with ROSI monotherapy, whereas 25/40 (63%) required ROSI and a sulfonylurea to meet this goal. Three of 40 (7.5%) had persistent insulin dependence. 25/40 (63%) continued on 4 mg/day of ROSI, and 15/40 (37%) required an increase to 8 mg/day. Mild edema developed in 13% of patients; significant weight gain did not occur.. Rosiglitazone is the first highly effective oral agent for PTDM. The majority of patients with PTDM may be safely treated with ROSI +/- a sulfonylurea. After the expected 3-6 week delay in the onset of ROSI action, most patients with PTDM will no longer require long-term insulin therapy.

Topics: Adult; Aged; Cyclosporine; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Insulin; Kidney Transplantation; Liver Transplantation; Male; Middle Aged; Organ Transplantation; PPAR gamma; Prospective Studies; Rosiglitazone; Tacrolimus; Thiazolidinediones

The present study investigated the incidence of posttransplant diabetes mellitus (PTDM) and calculated the risk of developing PTDM under a tacrolimus-based immunosuppression based on clinical characteristics, tacrolimus pharmacokinetics, and genetic polymorphisms related to tacrolimus pharmacokinetics or diabetes mellitus.. Seventy nondiabetic adult kidney recipients were studied. Patients with continuous high plasma glucose levels, over 6.5 mg/dl of hemoglobin A1c, or requiring insulin and/or oral antidiabetic agents for more than 3 months after transplantation 6 months postoperatively were diagnosed as having PTDM. Twelve genomic polymorphisms were assessed.. Six months after transplantation, 10 recipients (14.3%) developed PTDM. Positive risk factors were age (P=0.019) and body mass index (P=0.038). There were no significant differences in acute rejection rate, total steroid doses, tacrolimus pharmacokinetics or its related to genetic polymorphisms between the two groups. The frequency of PTDM was significantly higher in patients with the vitamin D receptor (VDR) TaqI t allele than in those with the TT genotype (P=0.013). On multivariate analysis, age over 50 years (odds ratio 9.28, P=0.003) and the presence of the VDR TaqI t allele (odds ratio 7.05, P=0.048) were correlated with the development of PTDM.. The incidence of PTDM was 14.3% in our cohort. Age over 50 years was a risk factor. The presence of the VDR TaqI t allele may also be a risk factor for PTDM, suggesting that genotyping of diabetes-related polymorphisms is a possible method of predicting a patient's risk for developing PTDM and would be a valuable asset in selecting appropriate immunosuppressive regimens for individuals.

Topics: Adiponectin; Adult; Azathioprine; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Diabetes Mellitus, Type 2; Female; Genes, MDR; Humans; Immunosuppressive Agents; Incidence; Ion Channels; Kidney Transplantation; Male; Membrane Transport Proteins; Middle Aged; Mitochondrial Proteins; Multivariate Analysis; Mycophenolic Acid; Peptidyl-Dipeptidase A; Polymorphism, Genetic; PPAR gamma; Receptors, Calcitriol; Risk Factors; Tacrolimus; Uncoupling Protein 2

New-onset diabetes mellitus after transplantation (NODAT) is a severe complication of kidney transplantation (KTx) with negative effects upon patient and graft survival. Several risk factors for NODAT have been described; however, the search for an early predictive marker is ongoing. It has recently been demonstrated that high concentrations of adiponectin (APN), which is an adipocyte-derived peptide with antiinflammatory and insulin-sensitizing properties, protect against future development of type 2 diabetes in healthy individuals. The purpose of this report was to study pretransplant insulin resistance and analyze pretransplant serum leptin and APN levels as independent risk factors for the development of NODAT.. A total of 68 KTx patients were studied [mean age, 48 +/- 11 years; 70% males; body mass index (BMI), 25 +/- 3 kg/m]; 31 KTx patients with NODAT and 37 KTx patients without NODAT (non-NODAT) with similar age, sex, BMI, immunosuppression, and posttransplant time were studied. All patients received prednisone and calcineurin inhibitors (75% tacrolimus and 25% cyclosporine A), and 76% of patients received mycophenolate mofetil. Family history of diabetes mellitus was recorded. Pretransplant homeostasis model assessment for insulin resistance (HOMA-IR) index was calculated from fasting plasma glucose and insulin. Pretransplant serum leptin and APN levels were determined by radioimmunoassay.. NODAT patients showed higher pretransplant plasma insulin concentrations [NODAT, 13.4 (11-22.7) microIU/mL; non-NODAT, 10.05 (7.45-18.4) microIU/mL; P=0.049], HOMA-IR index [NODAT, 4.18 (2.49-5.75); non-NODAT, 2.63 (1.52-4.68); P=0.043], and lower pretransplant serum APN concentration [NODAT, 8.78 (7.2-11.38) microg/mL; non-NODAT, 11.4 (8.56-15.27) microg/mL, P=0.012]. Inverse correlations between APN and BMI (r=-0.33; P=0.014) and APN and HOMA-IR index (r=-0.39; P=0.002) and between APN and NODAT (r=-0.31; P=0.011) were observed. Multiple logistic regression analysis showed the patients with lower pretransplant APN concentrations to be those at greater risk of developing NODAT [Odds Ratio=0.832 (0.71-0.96); P=0.01].. Pretransplant serum APN concentration is an independent predictive factor for NODAT development in kidney-transplanted patients.

Topics: Adiponectin; Adult; Blood Glucose; Diabetes Mellitus, Type 2; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Insulin; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Kidney Transplantation; Leptin; Male; Middle Aged; Multivariate Analysis; Postoperative Complications; Predictive Value of Tests; Proteins; Risk Factors; Tacrolimus

As the survival of renal transplant patients has increased, so has their risk of significant morbidity. Immunosuppressive drugs can exacerbate preexisting conditions and promote development of new disease. Effective long-term care of transplant recipients requires an understanding of how these drugs affect clinical evaluations and treatments.

Topics: Anti-Inflammatory Agents; Coronary Disease; Diabetes Mellitus, Type 2; Humans; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Prednisone; Risk Factors; Tacrolimus

Topics: Adolescent; Adult; Chronic Disease; Cyclosporine; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Graft Survival; Humans; Immunosuppressive Agents; Male; Middle Aged; Pancreas Transplantation; Pancreatitis; Retrospective Studies; Survival Rate; Tacrolimus; Time Factors

Topics: Adolescent; Adult; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Glucose Tolerance Test; Histocompatibility Testing; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Methylprednisolone; Postoperative Complications; Risk Factors; Tacrolimus; Time Factors

Topics: Blood Glucose; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Graft Survival; Hospitals, Veterans; Humans; Insulin; Liver Transplantation; Male; Methylprednisolone; Middle Aged; Pennsylvania; Tacrolimus

Topics: Anti-Bacterial Agents; Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Graft Rejection; Humans; Immunosuppressive Agents; Insulin; Liver Transplantation; Tacrolimus