Abstract: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 … Show more
“…TAC induced weight loss was common in the diabetic model, and vancomycin did not reverse it here. 42 , 43 No discernible differences in fasting glucose levels were observed among the three groups ( Figure 1b ). A set of tests was performed to assess the effects of TAC on glucose homeostasis and insulin sensitivity.…”
Up to 40% of transplant recipients treated long-term with tacrolimus (TAC) develop post-transplant diabetes mellitus (PTDM). TAC is an important risk factor for PTDM, but is also essential for immunosuppression after transplantation. Long-term TAC treatment alters the gut microbiome, but the mechanisms of TAC-induced gut microbiota in the pathogenesis of PTDM are poorly characterized. Here, we showed that vancomycin, an inhibitor of bacterial beta-glucuronidase (GUS), prevents TAC-induced glucose disorder and insulin resistance in mice. Metagenomics shows that GUS-producing bacteria are predominant and flourish in the TAC-induced hyperglycemia mouse model, with upregulation of intestinal GUS activity. Targeted metabolomics analysis revealed that in the presence of high GUS activity, the hydrolysis of bile acid (BAs)-glucuronic conjugates is increased and most BAs are overproduced in the serum and liver, which, in turn, activates the ileal farnesoid X receptor (FXR) and suppresses GLP-1 secretion by L-cells. The GUS inhibitor vancomycin significantly eliminated GUS-producing bacteria and inhibited bacterial GUS activity and BAs levels, thereby enhancing L-cell GLP-1 secretion and preventing hyperglycemia. Our results propose a novel clinical strategy for inhibiting the bacterial GUS enzyme to prevent hyperglycemia without requiring withdrawal of TAC treatment. This strategy exerted its effect through the ileal bile acid-FXR-GLP-1 pathway.
“…TAC induced weight loss was common in the diabetic model, and vancomycin did not reverse it here. 42 , 43 No discernible differences in fasting glucose levels were observed among the three groups ( Figure 1b ). A set of tests was performed to assess the effects of TAC on glucose homeostasis and insulin sensitivity.…”
Up to 40% of transplant recipients treated long-term with tacrolimus (TAC) develop post-transplant diabetes mellitus (PTDM). TAC is an important risk factor for PTDM, but is also essential for immunosuppression after transplantation. Long-term TAC treatment alters the gut microbiome, but the mechanisms of TAC-induced gut microbiota in the pathogenesis of PTDM are poorly characterized. Here, we showed that vancomycin, an inhibitor of bacterial beta-glucuronidase (GUS), prevents TAC-induced glucose disorder and insulin resistance in mice. Metagenomics shows that GUS-producing bacteria are predominant and flourish in the TAC-induced hyperglycemia mouse model, with upregulation of intestinal GUS activity. Targeted metabolomics analysis revealed that in the presence of high GUS activity, the hydrolysis of bile acid (BAs)-glucuronic conjugates is increased and most BAs are overproduced in the serum and liver, which, in turn, activates the ileal farnesoid X receptor (FXR) and suppresses GLP-1 secretion by L-cells. The GUS inhibitor vancomycin significantly eliminated GUS-producing bacteria and inhibited bacterial GUS activity and BAs levels, thereby enhancing L-cell GLP-1 secretion and preventing hyperglycemia. Our results propose a novel clinical strategy for inhibiting the bacterial GUS enzyme to prevent hyperglycemia without requiring withdrawal of TAC treatment. This strategy exerted its effect through the ileal bile acid-FXR-GLP-1 pathway.
“…Ling et al 18 demonstrated that tacrolimus directly (insulin signaling pathway) and indirectly (hepatic steatosis) leads to hepatic insulin resistance; another study revealed that adipocytokines and Peroxisome Proliferator-Activated Receptor Gamma signaling serve important roles in the pathogenesis of tacrolimus-induced insulin resistance. 19 Considering these effects of calcineurin inhibitors on insulin resistance, it may be reasonable to reduce the dosage of calcineurin inhibitors and to supplement with other immunosuppressants such as mammalian target of rapamycin inhibitors. Also, the changes in MI and HOMA-IR after pancreas transplantation may be affected by the surgical techniques.…”
Objectives: 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).
Methods:We analyzed 60 patients who underwent pancreas transplantation and oral glucose tolerance test pretransplant and at 1 month posttransplant.Results: 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.Conclusions: 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.
“…It has been reported that quadriceps are kinds of oxidative muscle which were closely related to insulin resistance [20] while the muscle fiber types of gastrocnemius are glycolytic type [20]. Our preliminary study had shown peroxisome proliferator-activated receptor-(PPAR-) γ which was related to insulin resistance in Tac-induced PTDM expressed in quadriceps [21]. So, quadriceps and gastrocnemius were dissected from the PTMD model induced by Tac to test this hypothesis.…”
Objective. Posttransplantation diabetes mellitus (PTDM) is a known complication of transplantation that affects the prognosis. Tacrolimus (Tac or FK506) is a widely used immunosuppressant that has been reported to be a risk factor for PTDM and to further induce complications in heart and skeletal muscles, but the mechanism is still largely unknown. In our preliminary experiments, we found that after Tac treatment, blood glucose increased, and the weight of skeletal muscle declined. Here, we hypothesize that tacrolimus can induce PTDM and influence the atrophy of skeletal muscle. Methods. We designed preliminary experiments to establish a tacrolimus-induced PTDM model. Gene expression profiles in quadriceps muscle from this rat model were characterized by oligonucleotide microarrays. Then, differences in gene expression profiles in muscle from PTDM rats that received tacrolimus and control subjects were analyzed by using GeneSpring GX 11.0 software (Agilent). Functional annotation and enrichment analysis of differentially expressed genes (DEGs) helped us identify clues for the side effects of tacrolimus. Results. Our experiments found that the quadriceps in tacrolimus-induced PTDM group were smaller than those in the control group. The study identified 275 DEGs that may be responsible for insulin resistance and the progression of PTDM, including 86 upregulated genes and 199 downregulated genes. GO and KEGG functional analysis of the DEGs showed a significant correlation between PTDM and muscle development. PPI network analysis screened eight hub genes and found that they were related to troponin and tropomyosin. Conclusions. This study explored the molecular mechanism of muscle atrophy in a tacrolimus-induced PTDM model by bioinformatics analyses. We identified 275 DEGs and identified significant biomarkers for predicting the development and progression of tacrolimus-induced PTDM.
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