Tacrolimus reversibly reduces insulin secretion, induces insulin resistance, and causes islet cell damage in rats

Xu, Chun; Yujian, Niu; Liu, Xiaojun; Teng, Yaqin; Li, Chunfeng; Wang, Hongyu; Yin, Junping; Wang, Le-Tian; Shen, Zhong-Yang

doi:10.5414/cp202090

Cited by 12 publications

(15 citation statements)

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“…Previous studies have found that calcineurin inhibitors impair glucose-stimulated insulin secretion in rodent islets and rodent cell lines ( 8 , 33-44 ), although through mechanisms that we show here are not validated in human islets. For example, we do not see evidence for a robust effect of TAC or VCS on insulin production or gene expression.…”

Section: Discussioncontrasting

confidence: 74%

Differential Effects of Voclosporin and Tacrolimus on Insulin Secretion From Human Islets

et al. 2020

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The incidence of new onset diabetes after transplant (NODAT) has increased over the past decade, likely due to calcineurin inhibitor-based immunosuppressants, including tacrolimus (TAC) and cyclosporin (CsA). Voclosporin (VCS), a next generation calcineurin inhibitor is reported to cause fewer incidences of NODAT but the reason is unclear. Whilst calcineurin signaling plays important roles in pancreatic β-cell survival, proliferation, and function, its effects on human β-cells remain understudied. In particular, we do not understand why some calcineurin inhibitors have more profound effects on the incidence of NODAT. We compared the effects of TAC and VCS on the dynamics of insulin secretory function, programmed cell death rate, and the transcriptomic profile of human islets. We studied two clinically relevant doses of TAC (10 ng/ml, 30 ng/ml) and VCS (20 ng/ml, 60 ng/ml), meant to approximate the clinical trough and peak concentrations. TAC, but not VCS, caused a significant impairment of 15 mM glucose-stimulated and 30 mM KCl-stimulated insulin secretion. This points to molecular defects in the distal stages of exocytosis after voltage-gated Ca 2+ entry. No significant effects on islet cell survival or total insulin content were identified. RNA sequencing showed that TAC significantly decreased the expression of 17 genes, including direct and indirect regulators of exocytosis (SYT16, TBC1D30, PCK1, SMOC1, SYT5, PDK4, and CREM), whereas VCS has less broad and milder effects on gene expression. Clinically relevant doses of TAC, but not VCS, directly inhibit insulin secretion from human islets, likely via transcriptional control of exocytosis machinery

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Section: Discussioncontrasting

confidence: 74%

Differential Effects of Voclosporin and Tacrolimus on Insulin Secretion From Human Islets

et al. 2020

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“…Insulin is released from pancreatic islets, in vivo and in vitro, in a biphasic pattern that includes both a rapid 1 st phase of pre-docked insulin granules and a 2 nd sustained phase involving granules that are recruited to the plasma membrane (27). There is significant inter-individual variability in the rate of insulin secretion from human islets (11) and the effects of immunosuppressants (7), so we examined insulin secretion from high quality human islets isolated from 17 donors exclusively for research purposes.…”

Section: Effects Of Tac or Vcs On Basal And Glucose Stimulated Insulimentioning

confidence: 99%

Differential effects of voclosporin and tacrolimus on insulin secretion from human islets

Kolic

Beet

Overby

et al. 2020

Preprint

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27Context. The incidence of new onset diabetes after transplant (NODAT) has increased over the 28 past decade. It has been suggested that NODAT is caused by exposure to calcineurin inhibitors, 29 particularly tacrolimus (TAC). Voclosporin (VCS), a next generation calcineurin inhibitor is 30 reported to cause fewer incidences of NODAT. 32Objective. Whilst calcineurin plays important roles in pancreatic -cell survival, proliferation, and 33 function, the effects of calcineurin inhibitors on human -cells remain understudied. In particular, 34 we do not understand why some inhibitors have more profound effects on the incidence of 35 NODAT. 37Design. Here, we compared the effects of TAC and VCS on the dynamics of insulin secretory 38 function, the programmed cell death rate, and the transcriptomic profile of human islets. We 39 studied two clinically relevant doses of TAC (10 ng/ml, 30 ng/ml) and VCS (20 ng/ml, 60 ng/ml), 40 meant to approximate the clinical trough and peak concentrations. 42Results. TAC, but not VCS, caused a significant impairment of 15 mM glucose-stimulated insulin 43 secretion and 30 mM KCl-stimulated insulin secretion. This points to molecular defects in the 44 distal stages of exocytosis after voltage-gated Ca2+ entry. No significant effects on islet cell 45 survival or total islet insulin content were identified. RNA sequencing showed that TAC, and to a 46 lesser extent VCS, decreased the expression of genes that regulate insulin exocytosis, trafficking, 47 and processing, including SYT16, SYT5, PITPNM1, and PAM. 49Conclusions. TAC directly inhibits insulin secretion, likely via transcriptional control of exocytosis 50 machinery. VCS was found to be gentler on isolated human islets than TAC. 51 54 steroids or high dose calcineurin inhibitors, particularly tacrolimus, on cell types that are critical 55 for the maintenance of glucose homeostasis (1). Tacrolimus (TAC; also known as FK506) is a 56 mainstay for prevention of transplant rejection, but effective immunosuppression targeting a 57 concentration range of 4-11 ng/mL still results in NODAT in > 20% of patients (2). There is an 58 unmet clinical need for calcineurin inhibitors that do not cause diabetes in this already vulnerable 59 patient population. 60Voclosporin (VCS) is a next-generation calcineurin inhibitor that is structurally related to 61 cyclosporine A (CsA) with the addition of a carbon molecule at amino acid-1 of (CsA). This 62 modification results in enhanced binding of the VCS-cyclophilin complex to calcineurin and shifts 63 metabolism, resulting in increased potency and a consistent pharmacokinetic-pharmacodynamic 64 profile as compared to (CsA). VCS was previously evaluated in a Phase IIb, multi-center, open-65 label, concentration-controlled study in patients undergoing de novo renal transplantation, 66 evaluating the efficacy and safety of three doses of VCS (0.4, 0.6, and 0.8 mg/kg BID) as 67 compared to TAC (3). In that study, the low-dose VCS group had similar efficacy to tacrolimus in 68 controlling acute rejection w...

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“…We could not obtain sufficient blood samples at the post-immunosuppression time point to check tacrolimus and insulin levels. Nonetheless, we employed an animal model with intraperitoneal injections of immunosuppressants known to develop hyperglycemia and insulin resistance with a dependable level of immunosuppression, similar to the human condition 27 – 29 . The probiotic treatment was attempted only as a proof-of-concept, hence immunosuppression was not maintained during this phase of the experiment.…”

Section: Discussionmentioning

confidence: 99%

“…All experiments were performed in accordance with the relevant guidelines and regulations. The rats were acclimated for 1 week, following which they were assigned to three experimental arms: intraperitoneal injections of (1) Tacrolimus at 2 mg/kg daily (n = 5 rats), (2) Sirolimus at 2.5 mg/kg daily (n = 5 rats), (3) control with DMSO injections (n = 4 rats) for 28 days 18 , 29 . These medications were reconstituted in saline for a total volume of 0.2 mL.…”

Section: Methodsmentioning

confidence: 99%

Impact of Immunosuppression on the Metagenomic Composition of the Intestinal Microbiome: a Systems Biology Approach to Post-Transplant Diabetes

Bhat

Pasini

Copeland

et al. 2017

Sci Rep

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Solid organ transplantation (SOT) outcomes have continued to improve, although long-term use of immunosuppressants can lead to complications such as diabetes, compromising post-transplant outcomes. In this study, we have characterized the intestinal microbiome (IM) composition at the metagenomic level in the context of hyperglycemia induced by immunosuppressants. Sprague-Dawley rats were subjected to doses of tacrolimus and sirolimus that reliably induce hyperglycemia and an insulin-resistant state. Subsequent exposure to probiotics resulted in reversal of hyperglycemia. 16S rRNA and metagenomic sequencing of stool were done to identify the bacterial genes and pathways enriched in immunosuppression. Bacterial diversity was significantly decreased in sirolimus-treated rats, with 9 taxa significantly less present in both immunosuppression groups: Roseburia, Oscillospira, Mollicutes, Rothia, Micrococcaceae, Actinomycetales and Staphylococcus. Following probiotics, these changes were reversed to baseline. At the metagenomic level, the balance of metabolism was shifted towards the catabolic side with an increase of genes involved in sucrose degradation, similar to diabetes. Conversely, the control rats had greater abundance of anabolic processes and genes involved in starch degradation. Immunosuppression leads to a more catabolic microbial profile, which may influence development of diabetes after SOT. Modulation of the microbiome with probiotics may help in minimizing adverse long-term effects of immunosuppression.

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Tacrolimus reversibly reduces insulin secretion, induces insulin resistance, and causes islet cell damage in rats

Cited by 12 publications

References 0 publications

Differential Effects of Voclosporin and Tacrolimus on Insulin Secretion From Human Islets

Differential Effects of Voclosporin and Tacrolimus on Insulin Secretion From Human Islets

Differential effects of voclosporin and tacrolimus on insulin secretion from human islets

Impact of Immunosuppression on the Metagenomic Composition of the Intestinal Microbiome: a Systems Biology Approach to Post-Transplant Diabetes

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