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FXR activation alleviates tacrolimus-induced post-transplant diabetes mellitus by regulating renal gluconeogenesis and glucose uptake.

ABSTRACT: BACKGROUND: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. METHODS: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 ? coactivator-1? (PGC1?) and forkhead box O1 (FOXO1) was detected by immunofluorescence. Human renal cortex proximal tubule epithelial cells (HK-2) were treated with 15 ?M FK506 or 4 ?M 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. RESULTS:FK506 significantly inhibited the mRNA and protein levels of FXR at 48 h and 72 h in HK-2 cells (P?

SUBMITTER: Li L

PROVIDER: S-EPMC6909577 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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FXR activation alleviates tacrolimus-induced post-transplant diabetes mellitus by regulating renal gluconeogenesis and glucose uptake.

Li Ling L Zhao Huijia H Chen Binyao B Fan Zhipeng Z Li Ning N Yue Jiang J Ye Qifa Q

Journal of translational medicine 20191213 1

<h4>Background</h4>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.<h4>Methods</h4>After C57BL/6J mice were treated with tacrolimus (FK506) for 3 months, the fasting b ...[more]

PMID: 31836014

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Project description:BACKGROUND: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. METHODS: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). RESULTS: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. CONCLUSIONS: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. TRIAL REGISTRATION:ClinicalTrials.gov NCT02108301.

Dataset Information

FXR activation alleviates tacrolimus-induced post-transplant diabetes mellitus by regulating renal gluconeogenesis and glucose uptake.

Publications

FXR activation alleviates tacrolimus-induced post-transplant diabetes mellitus by regulating renal gluconeogenesis and glucose uptake.

Similar Datasets

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