Deciphering Tacrolimus-Induced Toxicity in Pancreatic ß Cells.

ß 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 ß 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 ß cells, possibly by sharing common pathways of ß cell dysfunction. TAC-induced ß 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.

Proceedings from an international consensus meeting on posttransplantation diabetes mellitus: recommendations and future directions.

A consensus meeting was held in Vienna on September 8-9, 2013, to discuss diagnostic and therapeutic challenges surrounding development of diabetes mellitus after transplantation. The International Expert Panel comprised 24 transplant nephrologists, surgeons, diabetologists and clinical scientists, which met with the aim to review previous guidelines in light of emerging clinical data and research. Recommendations from the consensus discussions are provided in this article. Although the meeting was kidney-centric, reflecting the expertise present, these recommendations are likely to be relevant to other solid organ transplant recipients. Our recommendations include: terminology revision from new-onset diabetes after transplantation to posttransplantation diabetes mellitus (PTDM), exclusion of transient posttransplant hyperglycemia from PTDM diagnosis, expansion of screening strategies (incorporating postprandial glucose and HbA1c) and opinion-based guidance regarding pharmacological therapy in light of recent clinical evidence. Future research in the field was discussed with the aim of establishing collaborative working groups to address unresolved questions. These recommendations are opinion-based and intended to serve as a template for planned guidelines update, based on systematic and graded literature review, on the diagnosis and management of PTDM.

The higher diabetogenic risk of tacrolimus depends on pre-existing insulin resistance. A study in obese and lean Zucker rats.

Insulin resistance may interact with calcineurin inhibitors, enhancing the diabetogenic effect of tacrolimus compared with cyclosporine-A. We studied both drugs in insulin-resistant animals: obese Zucker rats (n = 45), and insulin-sensitive animals: lean Zucker rats (n = 21). During 11 days, animals received saline-buffer, cyclosporine-A (2.5 mg/kg/day) or tacrolimus (0.3 mg/kg/day). At Days 0 and 12 animals underwent intraperitoneal glucose tolerance test (0-30-60-120 min). Islet morphometry, beta-cell proliferation, apoptosis and Ins2 gene expression were analyzed. By Day 12, no lean animal had developed diabetes, while all obese animals on tacrolimus and 40% on cyclosporine-A had. In obese animals, tacrolimus reduced beta-cell proliferation and Ins2 gene expression compared with cyclosporine-A. Five days after treatment discontinuation, partial recovery was observed, with only 10% and 60% of the animals on cyclosporine and tacrolimus remaining diabetic respectively. Beta-cell proliferation increased in animals on tacrolimus while Ins2 gene expression remained unaltered. In conclusion, insulin resistance exacerbated the diabetogenic effect of tacrolimus compared with cyclosporine-A. This may be explained by greater inhibition of Ins2 gene and beta-cell proliferation by tacrolimus in the insulin resistant state. Discontinuation of the drugs may allow the recovery of the metabolic alterations.

Appetite stimulation with cannabis-based medicine and methods for assessment of glomerular filtration in older patients with medical illness: A study protocol.

BACKGROUND AND AIM: Malnutrition in older patients is linked to poor appetite. Cannabis-based medicine may have orexigenic properties in older patients, but this has to our knowledge never been investigated. In older patients, uncertainty applies to the accuracy of estimated glomerular filtration rate (eGFR) based on creatinine, which is crucial for medication prescribing. In older patients with poor appetite, the study aims (1) to assess the efficacy of Sativex® (8.1-mg delta-9-tetrahydrocannabinol [THC] and 7.5-mg cannabidiol [CBD]) to stimulate appetite and (2) to compare the performance of various GFR-estimates and measured-GFR (mGFR) for determining gentamicin clearance utilizing population pharmacokinetic (popPK) modelling methods. METHODS AND OBJECTIVES: This study is composed of two substudies. Substudy 1 is an investigator-initiated single-center, double-blinded, randomized, placebo-controlled, superiority, cross-over study. Substudy 1 will recruit 17 older patients with poor appetite, who will also be invited to substudy 2. Substudy 2 is a single-dose pharmacokinetics study and will recruit 55 patients. Participants will receive Sativex® and placebo in substudy 1 and gentamicin with simultaneous measurements of GFR in substudy 2. The primary endpoints are as follows: Substudy 1-the difference in energy intake between Sativex® and placebo conditions; substudy 2- the accuracy of different eGFR equations compared to mGFR. The secondary endpoints include safety parameters, changes in the appetite hormones, total ghrelin and GLP-1 and subjective appetite sensations, and the creation of popPK models of THC, CBD, and gentamicin.

[Metabolic syndrome and live kidney donor: is this syndrome a contraindication to donation?]. / Síndrome metabólico y donación renal de vivo: ¿contraindica la donación este síndrome?

Living donor kidney transplantation (KT) is the treatment of choice for end-stage renal disease patients and exhaustive assessment of the potential live kidney donor leads to successful KT in most occasions. Diabetes mellitus (DM), hypertension and obesity make up contraindications to donation because all of them are associated with postsurgical complications and future development of renal failure and cardiovascular (CV) disorders. However, it is unclear how much risk there is for individuals who donate a kidney and then develop some of these complications, which are grouped under the metabolic syndrome (MS.) Indeed, MS is a cluster of CV risk factors such as obesity, dyslipidemia, hypertension where the insulin resistance is the pathogenic mainstay. MS is an entity very prevalent in the western countries (20-30%) and has been associated with the development of CV disorders, DM and renal disease. Thus, it is crucial to detect MS before living donation in order to avoid these complications in the long-term. Regardless of clinical criteria to diagnosis MS, both oral glucose tolerance test and HbA1c levels may be useful clinical tools for unmasking MS before donation. Moreover, determination of insulin resistance by HOMA could help to achieve this objective. This review will outline the next issues: 1) frequency of MS in the general population (potentially, living kidney donor); 2) the impact of MS on DM, renal function and other CV complications; 3) assessment of living donor to unmask MS before donation; and 4) interventions on risk factors for minimizing MS-related threatening complications in the long-term. In any case, if MS is detected prior to donation, prophylactic and therapeutic measurement should be performed to avoid its progression. By contrast, MS could be considered a contraindication to donation.

Síndrome metabólico y donación renal de vivo: ¿este síndrome contraindica la donación? / No disponible

El trasplante renal con donante vivo constituye el tratamiento de elección para la insuficiencia renal crónica y la evaluación exhaustiva del donante garantiza el éxito del procedimiento. La Diabetes Mellitus (DM), la hipertensión arterial y la obesidad representan contraindicaciones clínicas para la donación de vivo, pero no se sabe con claridad cuál es el riesgo individual a largo plazo de un potencial donante que presenta alguna de estas alteraciones de origen metabólico agrupadas en el denominado Síndrome Metabólico (SM),donde la resistencia a la insulina constituye el nexo común etiopatogénico. El SM es muy prevalente en el mundo occidental (20-30%) y se asocia con el desarrollo de enfermedad cardiovascular, DM y alteraciones renales. De ahí la importancia de su detección antes de la donación, en aras de evitar tales complicaciones. Independientemente de la aplicación delos criterios clínicos para el diagnóstico del SM, realizar un test de sobrecarga oral de la glucosa, medir los niveles deHbA1cy evaluar la resistencia a la insulina mediante la determinación del HOMA pueden ayudarnos a desenmascarar este síndrome antes de la donación. En esta revisión, profundizaremos en: 1) la prevalencia del SM en la población general;2) el impacto del SM sobre la DM, la función renal y otras complicaciones cardiovasculares; 3) la evaluación que debe llevarse a cabo para descartar el SM ante la sospecha clínica del mismo; y 4) el tratamiento de los factores de riesgo de lSM para disminuir las consecuencias a largo plazo de esta complicación metabólica tras la donación. En cualquier caso, la detección del SM antes de la donación obliga a tomar las medidas profilácticas y terapéuticas oportunas para evitar su progresión. De no conseguirse este objetivo, el SM podría considerarse una contraindicación para la donación de vivo (AU)

Living donor kidney transplantation (KT) is the treatment of choice for end-stage renal disease patients and exhaustive assessment of the potential live kidney donor leads to successful KT in most occasions. Diabetes mellitus (DM), hypertension and obesity make up contraindications to donation because all of them are associated with post-surgical complications and future development of renal failure and cardiovascular (CV)disorders. However, it is unclear how much risk there is for individuals who donate a kidney and then develop some of these complications, which are grouped under the metabolic syndrome (MS). Indeed, MS is a cluster of CV risk factors such as obesity, dyslipidemia, hypertension where the insulin resistance is the pathogenic mainstay. MS is an entity very prevalent in the western countries (20-30%) and has been associated with the development of CV disorders, DM and renal disease. Thus, it is crucial to detect MS before living donation in order to avoid these complications in the long-term. Regardless of clinical criteria to diagnosis MS, both oral glucose tolerance test and HbA1clevels may be useful clinical tools for unmasking MS before donation. Moreover, determination of insulin resistance by HOMA could help to achieve this objective. This review will outline the next issues:1) frequency of MS in the general population (potentially, living kidney donor); 2) the impact of MS on DM, renal function and other CV complications; 3) assessment of living donor to unmask MS before donation; and 4) interventions on risk factors for minimizing MS-related threatening complications in the long-term. In any case, if MS is detected prior to donation, prophylactic and therapeutic measurement should be performed to avoid its progression. By contrast, MS could be considered a contraindication to donation. (AU)