tacrolimus and Prediabetic-State

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

Accumulating data indicate that sub-therapeutic levels of tacrolimus are associated with long-term kidney graft loss. However, elevated doses increase the risk of infection and drug toxicity, which also threaten graft and patient longevity. We sought to determine the minimal tacrolimus level required to maintain graft survival.. We conducted a single-center historical cohort study. The first-year post-transplant exposure time was calculated for each of the five tacrolimus trough level intervals. This measure was adjusted to the exposure time below a given interval level, allowing us to define the threshold for the optimal tacrolimus level as the upper limit of the interval. We then determined the association between the adjusted exposure time at each tacrolimus level interval and our primary outcome, death-censored graft loss.. One thousand four hundred and seventeen patients with a median follow-up of 5.3 years were included in the final cohort. The tacrolimus level interval of 5-6 ng/ml was the highest interval, which demonstrated a statistically significant association between adjusted exposure time and increased risk of graft loss (HR 1.58, per log days, p = .002). Cumulative exposure time above 14 days with a tacrolimus level below 6 ng/ml was associated with an increased rate of graft loss in most studied subgroups, except for recipients with pre transplant diabetes.. Maintaining tacrolimus levels above 6 ng/ml during the first-year post-transplant might improve kidney graft survival.

Topics: Cohort Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney; Prediabetic State; Tacrolimus

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

Immunosuppressive agents are associated with profound metabolic side effects including new-onset diabetes and dyslipidemia after organ transplantation.. To investigate the effects of cyclosporine A (CsA) and tacrolimus on glucose uptake and insulin signaling in human adipocytes and their impact on the regulation of cellular trafficking of the glucose transporter 4 (GLUT4).. Isolated human adipocytes were incubated with therapeutic concentrations of either CsA or tacrolimus, and glucose uptake and expression of insulin signaling proteins were assessed. Furthermore, we studied effects of CsA and tacrolimus on the regulation of cellular trafficking of GLUT4 in differentiated human preadipocytes and L6 cells.. CsA and tacrolimus had a concentration-dependent inhibitory effect on basal and insulin-stimulated (14)C-glucose uptake in adipocytes. Although phosphorylation at Tyr1146 of the insulin receptor was inhibited by tacrolimus, the phosphorylation and/or protein levels of the insulin signaling proteins IRS1/2, p85-PI3K, PKB, AS160, and mTORC1, as well as GLUT4 and GLUT1, were unchanged by CsA or tacrolimus. Furthermore, CsA and tacrolimus reduced the GLUT4 amount localized at the cell surface of differentiated human preadipocytes and L6 cells in the presence of insulin. This occurred by an increased rate of GLUT4 endocytosis, with no change in the exocytosis rate.. These results suggest that therapeutic concentrations of CsA and tacrolimus can inhibit glucose uptake independent of insulin signaling by removing GLUT4 from the cell surface via an increased rate of endocytosis. This mechanism can contribute to the development of insulin resistance and diabetes associated with immunosuppressive therapy. In addition, it may provide novel pharmacological approaches for the treatment of diabetes.

Topics: Adipocytes; Adipose Tissue; Adult; Aged; Blood Glucose; Cell Membrane; Cyclosporine; Endocytosis; Exocytosis; Female; Glucose Transporter Type 4; Humans; Immunosuppressive Agents; Insulin; Male; Membrane Proteins; Middle Aged; Myoblasts; Prediabetic State; Primary Cell Culture; Signal Transduction; Tacrolimus; Young Adult

Topics: Adipocytes; Cyclosporine; Endocytosis; Female; Glucose Transporter Type 4; Humans; Male; Prediabetic State; Tacrolimus

Post-transplant diabetes mellitus (PTDM), pre-diabetes-impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) are frequent complications after organ transplantation. The aim of this study was to assess the frequency of PTDM, IFG and IGT in a group of renal transplant recipients, to compare the frequency of glucose metabolism disorders in subjects treated with tacrolimus and with cyclosporine, and to establish the influence of different risk factors on the development of glucose metabolism disorders.. We examined 206 non-diabetic kidney allograft recipients (age 46.4 ± 12.3 years, time since transplantation 45.5 ± ± 33.6 months, BMI 26.3 ± 4.5 kg/m2). Glucose metabolism disorders were diagnosed using an oral glucose tolerance test. Logistic regression was used to assess the influence of each risk factor (age, BMI, waist circumference, physical activity, the presence of cardiovascular disease, positive family history of diabetes, cholesterol and triglycerides concentration) on the development of glucose metabolism disorders.. In 103 patients (50%), we diagnosed glucose metabolism disorders. 19% of patients had PTDM, 14% IFG, and 17% IGT. We did not find any differences in the frequency of glucose metabolism disorders between patients treated with tacrolimus and with cyclosporine. Multivariate analysis identified BMI and a family history of diabetes as independent risk factors of glucose metabolism disorders.. We found a high prevalence of glucose metabolism disorders in the examined group. This suggests that kidney transplant recipients should be screened for these disturbances. Patients with higher BMI and with first-degree relatives with diabetes had an increased risk of glucose metabolism disorders after kidney transplantation.

Topics: Blood Glucose; Cardiovascular Diseases; Causality; Comorbidity; Cyclosporine; Female; Glucose Metabolism Disorders; Glucose Tolerance Test; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Logistic Models; Male; Middle Aged; Obesity; Overweight; Prediabetic State; Risk Factors; Tacrolimus

Topics: Animals; Antibodies, Monoclonal; CD4 Antigens; Female; Fetal Tissue Transplantation; Graft Rejection; Immunosuppression Therapy; Islets of Langerhans Transplantation; Lymphocytes; Male; Mice; Mice, Inbred BALB C; Mice, Inbred CBA; Mice, Inbred NOD; Organ Culture Techniques; Prediabetic State; Swine; Tacrolimus; Transplantation, Heterologous