tacrolimus and Glucose-Intolerance

To explore the efficacy and safety of tacrolimus (TAC) combined with corticosteroids in patients with idiopathic membranous nephropathy (IMN).. A literature search was performed using Embase, Cochrane Library and PubMed from inception through May 31, 2021. All randomized controlled trials (RCTs) exploring the efficacy and safety of TAC combined with corticosteroids in IMN patients were included based on the inclusion and exclusion criteria. Data analyses were conducted using RevMan software (version 5.4).. Seven RCTs involving 520 patients were included in this meta-analysis. Compared with control treatment, TAC combined with corticosteroids could significantly increase the complete remission (CR) rate, total remission (TR) rate, and serum albumin levels, as well as decrease the proteinuria levels within 6-month treatment, but the advantage did not persist to 12-month treatment. After 18-month treatment, the effect of TAC combined with corticosteroids on increasing CR rate, TR rate, and serum albumin levels was significantly worse than control treatment. The mean time to remission in TAC combined corticosteroids group was significantly shorter than that in the control group. The relapse rate, no response rate, change in estimate of the glomerular filtration rate (eGFR), and overall incidence of adverse reactions showed no significant difference between TAC combined with corticosteroids group and control group. However, TAC combined with corticosteroids did have a higher risk of hand tremor, nephrotoxicity, and glucose intolerance than control treatment.. TAC combined with corticosteroids has a significant therapeutic effect for IMN patients within 1-year treatment, especially in the first 6 months. However, in the longer-term treatment, TAC combined with corticosteroids does not have an advantage. TAC combined with corticosteroids has a higher risk of hand tremor, nephrotoxicity, and glucose intolerance. More high-quality studies are needed to further verify the long-term efficacy and safety of TAC combined with glucocorticoids in IMN patients.

Topics: Adrenal Cortex Hormones; Drug Therapy, Combination; Glomerulonephritis, Membranous; Glucose Intolerance; Humans; Immunosuppressive Agents; Randomized Controlled Trials as Topic; Serum Albumin; Tacrolimus; Treatment Outcome; Tremor

Topics: Adult; Calcium; Cyclic ADP-Ribose; Cyclosporine; Diabetic Coma; Glucose Intolerance; Humans; Immunosuppressive Agents; Insulin; Insulin Secretion; Islets of Langerhans; Male; RNA, Messenger; Tacrolimus; Transcription, Genetic

Topics: Animals; Brain; Calcineurin; Calcineurin Inhibitors; Calcium Channels; Cell Death; Cyclosporine; Cytokines; DNA-Binding Proteins; Glucose Intolerance; Humans; Immunosuppressive Agents; Lymphocyte Activation; Neurons; NFATC Transcription Factors; Nuclear Proteins; Signal Transduction; T-Lymphocytes; Tacrolimus; Transcription Factors

The purpose of the study is to evaluate the efficiency and safety of tacrolimus (TAC) monotherapy in the treatment of nephrotic idiopathic membranous nephropathy (IMN) compared with the protocol of cyclophosphamide (CTX) combined with corticosteroids.. Twelve months after the initial treatment, a total of 24 (80%) patients in the TAC group and 23 (82.1%) patients in the CTX group achieved remission (either partial or complete remission). The survival curve of the probability of remission and complete remission were similar between the two groups (p > .05). Proteinuria (based on 24 h urinary protein excretion) was significantly decreased, and serum albumin was significantly increased after immunosuppressive treatment in both the groups. Estimated glomerular filtration rate (eGFR) was comparable between before and after treatment. The main adverse effects in TAC treatment were glucose intolerance, diabetes and abnormal aminotransferase.. TAC monotherapy is an alternative therapeutic regimen for patients with nephrotic IMN. Its short-term efficiency and patient tolerance are both acceptable.

Topics: Adult; Cyclophosphamide; Diabetes Mellitus; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Glomerulonephritis, Membranous; Glucocorticoids; Glucose Intolerance; Humans; Immunosuppressive Agents; Kidney; Male; Middle Aged; Nephrotic Syndrome; Prednisone; Prospective Studies; Proteinuria; Remission Induction; Serum Albumin; Tacrolimus; Treatment Outcome

Topics: Administration, Oral; Blood Glucose; Diabetes Mellitus; Dose-Response Relationship, Drug; Drug Therapy, Combination; Glucose Intolerance; Humans; Immunosuppressive Agents; Kidney Transplantation; Metabolic Clearance Rate; Prednisolone; Regression Analysis; Tacrolimus

Macroautophagy/autophagy or mitophagy plays crucial roles in the maintenance of pancreatic β-cell function. PPP3/calcineurin can modulate the activity of TFEB, a master regulator of lysosomal biogenesis and autophagy gene expression, through dephosphorylation. We studied whether PPP3/calcineurin inhibitors can affect the mitophagy of pancreatic β-cells and pancreatic β-cell function employing FK506, an immunosuppressive drug against graft rejection. FK506 suppressed rotenone- or oligomycin+antimycin-A-induced mitophagy measured by Mito-Keima localization in acidic lysosomes or RFP-LC3 puncta colocalized with TOMM20 in INS-1 insulinoma cells. FK506 diminished nuclear translocation of TFEB after treatment with rotenone or oligomycin+antimycin A. Forced TFEB nuclear translocation by a constitutively active TFEB mutant transfection restored impaired mitophagy by FK506, suggesting the role of decreased TFEB nuclear translocation in FK506-mediated mitophagy impairment. Probably due to reduced mitophagy, recovery of mitochondrial potential or quenching of mitochondrial ROS after removal of rotenone or oligomycin+antimycin A was delayed by FK506. Mitochondrial oxygen consumption was reduced by FK506, indicating reduced mitochondrial function by FK506. Likely due to mitochondrial dysfunction, insulin release from INS-1 cells was reduced by FK506 in vitro. FK506 treatment also reduced insulin release and impaired glucose tolerance in vivo, which was associated with decreased mitophagy and mitochondrial COX activity in pancreatic islets. FK506-induced mitochondrial dysfunction and glucose intolerance were ameliorated by an autophagy enhancer activating TFEB. These results suggest that diminished mitophagy and consequent mitochondrial dysfunction of pancreatic β-cells contribute to FK506-induced β-cell dysfunction or glucose intolerance, and autophagy enhancement could be a therapeutic modality against post-transplantation diabetes mellitus caused by PPP3/calcineurin inhibitors.

Topics: Antimycin A; Autophagy; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Calcineurin Inhibitors; Glucose Intolerance; Humans; Insulins; Lysosomes; Mitophagy; Oligomycins; Rotenone; Tacrolimus

Post‑transplantation diabetes mellitus (PTDM) is a known side effect in transplant recipients administered with immunosuppressant drugs, such as tacrolimus (Tac). Although injury of islet cells is considered a major reason for Tac‑induced PTDM, the involvement of insulin resistance in PTDM remains unknown. In the present study, expression levels of adipocytokines, glucose metabolism associated genes and peroxisome proliferator‑activated receptor (PPAR)‑γ in adipose, muscular and liver tissues from a rat model induced with Tac (1 mg/kg/day) were examined. Rats developed hyperglycemia and glucose intolerance after 10 days of Tac administration. A subgroup of diabetic rats was further treated with rosiglitazone (4 mg/kg), a PPAR‑γ activator. Adipose, muscle and liver tissues were obtained on day 15 after induction and the results demonstrated that expression levels of adipocytokines, PPAR‑γ and proteins in the insulin associated signaling pathway varied in the different groups. Rosiglitazone administration significantly improved hyperglycemia, glucose intolerance and expression levels of proteins associated with insulin signaling, as well as adipocytokines expression. The results of this study demonstrated that adipocytokines and PPAR‑γ signaling may serve important roles in the pathogenesis of Tac‑induced PTDM, which may provide a promising application in the treatment of PTDM in the future.

Topics: Animals; Biomarkers; Carbohydrate Metabolism; Diabetes Mellitus, Experimental; Disease Models, Animal; Gene Expression; Gene Expression Regulation; Glucose; Glucose Intolerance; Immunosuppressive Agents; Insulin; Male; Organ Specificity; Organ Transplantation; Rats; Signal Transduction; Tacrolimus

Tacrolimus is an established immunosuppressant for the prevention and treatment of allograft rejection in organ transplantation. However, tacrolimus therapy also has several adverse effects. The main aim of this study was to evaluate the effect of conversion from twice-daily tacrolimus (tacrolimus-BID) to once-daily tacrolimus (tacrolimus-OD) on glucose intolerance in stable kidney transplant patients.. The study comprised 43 kidney transplant recipients with stable renal function. The same 1 mg:1 mg dose conversion was used for all patients. Follow-up, which included clinical evaluation and laboratory testing, was performed at 30, 60, and 120 days after conversion. The parameters for which the baseline and end-point values were determined included homeostasis model assessment of beta-cell function (HOMA-B) scores, hemoglobin A(1c) (HbA(1c)) levels, serum insulin levels, and fasting glucose levels.. The tacrolimus trough levels did not differ significantly at 120 days after conversion. There was a significant increase in serum insulin level at 120 days after conversion (baseline, 5.6 ± 2.7 μU/mL; end point, 6.6 ± 3.4 μU/mL; P < .009). The HOMA-B score slightly increased (baseline, 58.7 ± 33.1; end point, 65.6 ± 32.8; P = .091) at 120 days after conversion, indicating beta-cell function. Serum creatinine concentration, blood glucose level, and HbA(1c) level did not change significantly during follow-up examinations. Episodes of acute rejection or graft loss did not occur.. The results of this study suggests that conversion from tacrolimus-BID to tacrolimus-OD may benefit kidney transplant patients with glucose intolerance because of improved insulin secretion. Further studies involving a larger sample population and longer follow-up time are required to verify the results of this study.

Topics: Adult; Biomarkers; Blood Glucose; Drug Administration Schedule; Female; Glucose Intolerance; Glycated Hemoglobin; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Insulin; Insulin-Secreting Cells; Japan; Kidney Transplantation; Male; Middle Aged; Tacrolimus; Time Factors; Treatment Outcome

Most degenerative diseases begin with a gradual loss of specific cell types before reaching a threshold for symptomatic onset. However, the endogenous regenerative capacities of different tissues are difficult to study, because of the limitations of models for early stages of cell loss. Therefore, we generated a transgenic mouse line (Mos-iCsp3) in which a lox-mismatched Cre/lox cassette can be activated to produce a drug-regulated dimerizable caspase-3. Tissue-restricted Cre expression yielded stochastic Casp3 expression, randomly ablating a subset of specific cell types in a defined domain. The limited and mosaic cell loss led to distinct responses in 3 different tissues targeted using respective Cre mice: reversible, impaired glucose tolerance with normoglycemia in pancreatic β cells; wound healing and irreversible hair loss in the skin; and permanent moderate deafness due to the loss of auditory hair cells in the inner ear. These mice will be important for assessing the repair capacities of tissues and the potential effectiveness of new regenerative therapies.

Topics: Alopecia; Animals; Apoptosis; Caspase 3; Cell Lineage; Dimerization; Disease Models, Animal; Epidermis; Gene Expression Regulation; Gene Knockdown Techniques; Genes, Transgenic, Suicide; Glucose Intolerance; Hair Cells, Auditory, Inner; Hearing Loss, Bilateral; Hearing Loss, Sensorineural; Homeodomain Proteins; Insulin; Islets of Langerhans; Keratin-14; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mosaicism; Organ Specificity; Phenotype; Tacrolimus; Transcription Factor Brn-3C; Transgenes; Wound Healing

Most reported data on posttransplantation diabetes mellitus (PTDM) are from Western countries with patients who underwent deceased donor liver transplantation. A retrospective study was performed to assess the prevalence and predictive factors of PTDM in the context of living donor liver transplantation (LDLT) in the Chinese population using the definition of PTDM proposed in 2003 by the World Health Organization and the American Diabetes Association. The prevalence of DM after LDLT in our study was 25% (21/84), and the incidence of PTDM was 14.9% (11/74) with 64% of cases diagnosed within 3 months after LDLT; 9.5% were observed to show impaired fasting glucose postoperatively. Multivariate analysis identified body mass index >or= 25 kg/m(2) before LDLT as the only independent risk factor for developing PTDM. Only one patient was operated for hepatitis C virus (HCV) infection. Hepatitis B virus (HBV)-related diseases were common in our study population, accounting for 78.6% of all patients. Both HCV and HBV infection status were not independent risk factors for developing PTDM. In addition, a greater tacrolimus trough blood level in the PTDM group versus no-DM group was observed at 3 months post-LDLT (11.03 ng/mL vs 4.87 ng/mL). The mean tacrolimus dose was not significantly different between the two groups. In conclusion, PTDM was prevalent among Chinese LDLT recipients.

Topics: Adult; Blood Glucose; China; Diabetes Mellitus; Female; Glucose Intolerance; Hepatitis B; Hepatitis C; Humans; Immunosuppressive Agents; Incidence; Liver Transplantation; Living Donors; Male; Middle Aged; Multivariate Analysis; Odds Ratio; Postoperative Complications; Prevalence; Retrospective Studies; Risk Factors; Tacrolimus

Tacrolimus is an immunosuppressive drug that causes glucose intolerance. On the other hand, ciprofloxacin, which is widely used in the treatment of infectious diseases, is known to cause hypoglycemia as a side effect. We investigated the effects of tacrolimus and ciprofloxacin on serum glucose and insulin levels in rats, as well as on insulin secretion and the viability of HIT-T15 cells. The rats received intraperitoneal injections of tacrolimus and/or ciprofloxacin for 1 week, and their arterial blood was sampled after the administration of glucose. HIT-T15 cells were cultured in the presence of tacrolimus and/or ciprofloxacin, and the insulin level in the supernatant was measured. Ciprofloxacin did not show a significant effect on serum glucose and insulin levels after multiple administrations in the rats. In contrast, rats in the tacrolimus treatment group showed low serum insulin and high serum glucose levels. Moreover, the coadministration of ciprofloxacin and tacrolimus resulted in higher glucose levels compared with tacrolimus alone 0.5 h after glucose stimulation. In addition, we observed that the rats administered tacrolimus and/or ciprofloxacin had low body weight and food intake. Tacrolimus caused a dose-dependent decrease in the viability of the HIT-T15 cells. Furthermore, both drugs were highly toxic to HIT-T15 cells. In contrast, tacrolimus alone and coadministration of the drugs resulted in no significant difference in insulin secretion. These results suggest that the cytotoxic effects of ciprofloxacin and tacrolimus cause a decrease in insulin secretion, leading to glucose intolerance.

Topics: Animals; Anti-Infective Agents; Body Weight; Cell Survival; Cells, Cultured; Ciprofloxacin; Cricetinae; Dose-Response Relationship, Drug; Eating; Glucose; Glucose Intolerance; Hypoglycemia; Immunosuppressive Agents; Insulin; Insulin-Secreting Cells; Male; Rats; Rats, Wistar; Tacrolimus

The safety and efficacy of tacrolimus (Tac)-based immunosuppressive treatments were studied in 115 pediatric renal transplant recipients (mean follow-up period, approximately 20 months). The acute rejection rate was 22.7% 6 months after transplantation and the steroid-resistant acute rejection rate was 6.4%. The 5-year patient and graft survival rates were 98.6% and 95.9%, respectively. Major adverse effects included infection, ie, cytomegalovirus (CMV) antigenemia (41.7%), renal dysfunction (29.6%), and impaired glucose tolerance (20.9%). The incidences of these adverse events were significantly decreased among patients who had undergone transplantation after March 2000 (n = 43), namely, 30.2%, 18.6%, and 11.6%, respectively.

Topics: Adult; Cadaver; Female; Follow-Up Studies; Glucose Intolerance; Graft Rejection; Humans; Immunosuppressive Agents; Infections; Japan; Kidney Transplantation; Living Donors; Male; Nervous System Diseases; Postoperative Complications; Retrospective Studies; Survival Analysis; Tacrolimus; Time Factors; Tissue Donors

We describe the generation and characterization of the first inducible 'fatless' model system, the FAT-ATTAC mouse (fat apoptosis through targeted activation of caspase 8). This transgenic mouse develops identically to wild-type littermates. Apoptosis of adipocytes can be induced at any developmental stage by administration of a FK1012 analog leading to the dimerization of a membrane-bound, adipocyte-specific caspase 8-FKBP fusion protein. Within 2 weeks of dimerizer administration, FAT-ATTAC mice show near-knockout levels of circulating adipokines and markedly reduced levels of adipose tissue. FAT-ATTAC mice are glucose intolerant, have diminished basal and endotoxin-stimulated systemic inflammation, are less responsive to glucose-stimulated insulin secretion and show increased food intake independent of the effects of leptin. Most importantly, we show that functional adipocytes can be recovered upon cessation of treatment, allowing the study of adipogenesis in vivo, as well as a detailed examination of the importance of the adipocyte in the regulation of multiple physiological functions and pathological states.

Topics: Adipocytes; Adipose Tissue; Animals; Apoptosis; Caspase 8; Caspases; Dimerization; Eating; Enzyme Activation; Glucose Intolerance; Inflammation; Insulin; Insulin Secretion; Leptin; Lipodystrophy; Lipopolysaccharides; Mice; Mice, Transgenic; Recombinant Fusion Proteins; Tacrolimus; Tacrolimus Binding Proteins

Topics: Adult; Diabetes Mellitus; Female; Glucose Intolerance; Glucose Tolerance Test; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Male; Postoperative Complications; Retrospective Studies; Tacrolimus

To evaluate the impact of acute and chronic liver disease and single immunosuppression (cyclosporine A [CSA] or FK506) on insulin sensitivity and glucose effectiveness in liver-grafted patients, we performed a frequently sampled intravenous glucose tolerance test (FSIGTT) in nondiabetic patients after orthotopic liver transplantation (OLT) with acute liver failure ([ALF] group, n = 9, with CSA therapy), in patients after OLT with chronic liver disease (CSA group, n = 8; FK506 group, n = 8), and in 9 healthy control subjects. Insulin sensitivity and glucose effectiveness were determined by analyzing glucose and insulin data from the FSIGTT with Bergman's minimal model technique for glucose. The intravenous glucose tolerance index ([KG] ie, the slope of the regression of the logarithm of blood glucose concentration) was not different between the ALF group (2.17 +/- 0.16 min(-1)) and controls (2.29 +/- 0.13 min(-1)), but was lower (P < .05) in both groups with chronic liver disease (CSA group, 1.46 +/- 0.1; FK506 group, 1.61 +/- 0.11 min(-1)) compared with the ALF group (P < .05). A positive relation for the KG and glucose effectiveness was found in all liver-grafted patients and controls. Insulin sensitivity was not different between all liver-grafted patients and controls. The body mass index (BMI) was the overall determinant of insulin sensitivity in all groups. Single immunosuppressive therapy does not impair insulin sensitivity in liver-grafted patients. The lower glucose effectiveness in liver-grafted patients with chronic liver disease but not in patients after ALF points to a defect in the regulation of glucose-mediated glucose uptake in peripheral tissue.

Topics: Adult; Blood Glucose; Cholesterol; Cyclosporine; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Immunosuppressive Agents; Insulin; Liver Cirrhosis; Liver Failure, Acute; Liver Transplantation; Male; Models, Biological; Postoperative Complications; Reference Values; Tacrolimus; Triglycerides

Living renal transplantation (Tx) was carried out on a 41-year-old male undergoing hemodialysis for a six-month period because of end-stage renal failure due to chronic glomerulonephritis. Tacrolimus (FK 506) was used as one of immunosuppressants. The graft worked immediately after Tx. However, his blood sugar level rose extremely high and use of insulin (IS) was required. At the second postoperative day, 0.3 mg/kg/day of FK506 was administered and the trough level (TL) was as high as 65 ng/ml. The serum IS level decreased from the pre-Tx value of 22 microU/ml to 12 microU/ml. With decrease in the dose of FK506, the TL was normalized, and the dose of IS could be decreased. FK506 has been reported to inhibit IS secretion. Therefore, we must be careful to evaluate the blood glucose level in the use of FK506 for patients with poor glucose tolerance.

Topics: Adult; Chronic Disease; Diabetes Mellitus; Glomerulonephritis; Glucose Intolerance; Humans; Kidney Transplantation; Male; Renal Dialysis; Tacrolimus; Transplantation, Homologous

To clarify the mechanism of glucose intolerance induced by FK506, a novel immunosuppressant, 5 or 10 mg/kg/day of FK506 was dosed orally to rats for 2 weeks, and 125I-insulin binding to the erythrocytes, plasma glucose and insulin levels, and pancreatic insulin content were examined. Insulin binding to the erythrocytes of rat dosed with FK506 was similar to that to erythrocytes of the placebo control; Scatchard analysis confirmed that FK506 did not cause damage to the insulin receptor of the erythrocytes. Contrarily, FK506 caused a clear decrease of pancreatic insulin content as well as a slight decrease of plasma insulin level. The results suggest that the glucose intolerance induced by FK506 is associated with a decrease of insulin secretion, but is not associated with impairment of the insulin receptor.

Topics: Animals; Blood Glucose; Erythrocytes; Glucose Intolerance; Insulin; Male; Pancreas; Protein Binding; Rats; Rats, Sprague-Dawley; Receptor, Insulin; Tacrolimus

Topics: Cyclosporine; Glucose Intolerance; Graft Rejection; Humans; Hyperglycemia; Liver Transplantation; Tacrolimus