Influence on survival and replication of beta-cells
Calcineurin and its signaling pathway is biologically significant for many tissues. In beta-cells, calcineurin phosphatase activity has at least 2 well-known targets: Nuclear factor of activated T-cell (NFAT) and co-activator of CAMF-dependent transcription factor (cAMP response element-binding protein, CREB) – protein TORC2 (transducer of regulated CREB activity 2). Forming complexes with FK506-binding protein 1B and cyclophilin respectively, tocralimus and cyclosporine A are linked with calcineurin, inhibiting it and its signaling pathway[41]. Thus, calcineurin inhibition may lie in the basis of development of PTDM caused by direct toxic effect of tocralimus and cyclosporine A.
Plaumann S. Et al. Indicated that, while inhibiting calcineurine, cyclosporine activates dual leucine-zipper-bearing kinase (DLK), which leads to beta-cells apoptosis [42]. Tocralimus reduces phosphorylation of Akt kinase of PI3K/AKT signaling pathway which influences on beta-cells growth and proliferation. Besides, number of mRNA and protein of insulin receptor substrate-2 (Irs2) is decreased, which is, probably, caused by calcineurin inhibition, as NFAT, dephosphorylated by calcineurin, activates Irs2 transcription [43].
Influence on insulin secretion and its effect
It was indicated In vitro and in vivo that pharmacologic calcineurin inhibition suppresses insulin secretion and is dose-dependent [41].
Clinical study indicated that the effect of tocralimus on insulin secretion may be connected with high concentration of the preparation in the blood. The concentration decrease improves beta-cells functioning. In decrease of tocralimus concentration from 9,5 to 6,4 ng/ml, the level of S-peptide has grown from 49.0 to 66.6 nmole/l, P=0.04 [41]. In the published study, beta-cells secretory activity remained normal in renal graft or combined transplantation recipients who got a low dosage of glucocorticoids, (5 mg per day) and moderate tocralimus dosage (concentration in the blood was limited by 6 - 10 mkg/l) [44].
Mitochondria play the key role in insulin secretion. Cyclosporine is linked with cyclophilin D in mitochondrial transitory pores (MTP) and blocks opening of these channel, free cytoplasmic calcium concentration, which causes damage to glucose-stimulated insulin secretion [41]. Rostambeigi N. Et al. Demonstrated that tocralimus may inhibit expression of genes which take part in cytoskeleton building, membrane transportation, ATP production and regulation of mitochondrial functions, which influences on insulin secretion [45]. Both tocralimus, and cyclosporine A impare glucose-stimulated insuline secretion, inhibiting closure of ATP-dependent potassium channels. Tocralimus also reduces glucokinase activity and insulin exocytosis, by influencing on the level of intracellular calcium [41].
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Some trials indicate that calcineurin inhibitors increase insulin-resistance. Calcineurin inhibition prevents activation of genes participating in muscular remodeling: MEF-2 gene (myocyte enhancer factor- 2) leads to increase in insulin-resistance in muscular fibers, decrease in expression of PGC-1 gene (perisome proliferator activated receptor gamma activator-1) reduces insulin-sensitivity in skeletal muscles [46]. However, the mechanisms of insulin-resistance development are subject to further studies.
(I)
(II)
Fig.1. Influence of calcineurin inhibitors on beta-cell functioning (adapted scheme [41]).
TAC – tocralimus; FKBP1B - FK-binding protein 1B; CsA – cyclosporine A; CiF– cyclophilin; DLK – kinase baring dual leucine zipper; mTORC2 – mTOR complex 2; CREB – transcriptory factor; MTP– mitochondrial transitory pores; NFAT – nuclear factor of activated Т-cells; Г-6-F –glucose-6-phosphatase; PI3K – phosphoinositide-3-kinase
I -Tocralimus.
а) Calcineurin dephosphorylates nuclear factor of activated T-cells (NFAT) and CREB. Dephosphorylation of these proteins regulates expression of several genes-targets which influence on beta-cells development replication and functioning. Forming the complex with cytoplasmic receptor FK-binding protein 1B, tacrolimus inhibits calcineurin which reduces beta-cells replication and survivability.
б) Tacrolimus may inhibit expression of genes which participate in cytoskeleton remodeling, as well as membrane transportation, ATP production and regulation of mitochondrial function, which influences on insulin secretion.
в) Tacrolimus resists closure of ATP-sensitive potassium channels, which suppresses glucose-dependent insulin secretion.
г) Tacrolimus reduces glucokinase activity which decreases ATP production, which also influences glucose-dependent insulin secretion.
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д) Tacrolimus also influences on increase of intracellular calcium level, which impairs insulin exocytosis.
II –Cyclosporine A.
а) Cyclosporine A (CsA) is linked with cytoplasmic receptor- cyclophilin. The complex of Cyclosporine A and cyclophilin inhibits calceneurin.
б) In view of calcineurin inhibition, DLK-kinase (dual leucine-zipper-bearing kinase) is activated, which induces beta-cell apoptosis.
в) CsA is linked with cyclophilin D in mitochondrial transitory pores and blocks opening of these channels reducing free cytoplasmic calcium concentration, which, in turn, impairs glucose-stimulated insulin secretion.
г) CsA resists closure of ATP-sensitive potassium channels which suppresses glucose-dependent insulin secretion.
PTDM, ASSOCIATED WITH mTOR INHIBITORS
Mammalian target of rapamycin (mTOR) – serine-threonine specificity protein kinase consisting of 2 complexes [mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2)]. It participates in regulation of cellular growth and survival. Sirolimus (rapamycin) is macrolide which inhibits T-cellular activation linking with FK506 binding protein 1V (FK506-BP1B); the formed complex inhibits mTOR.
More and more data evidence that serolimus has diabetogenic effect. According to USRDS data, connection between serolimus application and PTDM development among 20124 recipients with renal transplantation, was defined [47].
As compared to patients getting cyclosporine combined with mycophenolat mophityl, or azathioprine, in patients getting serolimus combined with cyclosporine, tacrolimus, mycophenolate mophityl or azathioprine, the risk of PTDM development was higher.
It was shown in animal models that the effect of sirolimus on beta-cells functioning has a paradoxical nature. In therapeutic dosage, serolimus significantly intensifies both basal (50%), and glucose-induced (40%) insulin secretion in pygmy pigs [41].
Serolimus also increases insulin content in islets of Langerhans in a human [41].
However, suppression of insulin secretion by serolimus is also reported if the dosage exceeds therapeutic one. The study indicated that, similar to calcineurin inhibitors, sirolimus may also suppress insulin secretion by inhibiting closure of ATP-dependent potassium channels [48].
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In another study, made on rats serolimus was indicated to suppress glucose-stimulated insulin secretion, inhibiting Krebs cycle, which reduces mitochondrial ATP production [49].
There is also strong evidence that serolimus may impair beta-cells regeneration and proliferation. Because of inhibiting mTORC1 and its signaling pathway which regulates 4E-binding protein translation (4EBP — eukaryotic translation initiation factor 4E binding protein) and S6K — ribosomal S6 kinase [50], beta-cells proliferation is impaired. Besides, mTORC2 signaling pathway which includes Akt phosphorylation and activation, also has a significant meaning in beta-cells functioning [51].
Figure 2 shows the scheme of possible ways of serolimus diabetogenic effect.
Fig. 2. Influence of mTOR inhibitors on beta-cell functioning (the scheme is adapted [41]).
mTOR – Mammalian target of rapamycine; SRL – serolimus; S6K, ribosomal S6 kinase; FKBP1B, FK-506-binding protein 1B. 4EBP, 4E-binding protein; mTORS1 – mTOR complex 1; mTORC2 – mTOR complex 2.
mTORC1 signaling pathway regulates 4EBP1-binding protein translation (4EBP1 — eukaryotic translation initiation factor 4E binding protein) and S6K1 — ribosomal S6 kinase which participate in beta-cells growth and proliferation. mTORC2 participates in Akt phosphorylation and activation and therefore, plays an important role in cells survival. Serolimus impairs cellular regeneration and proliferation mainly through inhibiting mTORS1 (a), and, probably, mTORS2 (b). Serolimus also reduces ATP mitochondrial production by suppressing Krebs cycle (c) and inhibits closure of ATP-dependent potassium channels (d which impairs glucose-dependent insulin secretion).
EFFECT OF OTHER IMMUNE-SUPPRESSIVE PREPARATIONS
Diabetogenic effect of azathioprine and inosine-monophosphat- dehydrogenase of mycophenolate mophityl (MMF) antimetabolite has not been revealed. On the contrary, simultaneous application of MMF is suggested to soften diabetogenic influence of tacrolimus [13]. Use of azathioprine and MMF enable to apply lower dosage of other immunosuppressors which have diabetogenic effect.
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