Abstract:
:Active maintenance of β-cell identity through fine-tuned regulation of key transcription factors ensures β-cell function. Tacrolimus, a widely used immunosuppressant, accelerates onset of diabetes after organ transplantation, but underlying molecular mechanisms are unclear. Here we show that tacrolimus induces loss of human β-cell maturity and β-cell failure through activation of the BMP/SMAD signaling pathway when administered under mild metabolic stress conditions. Tacrolimus-induced phosphorylated SMAD1/5 acts in synergy with metabolic stress-activated FOXO1 through formation of a complex. This interaction is associated with reduced expression of the key β-cell transcription factor MAFA and abolished insulin secretion, both in vitro in primary human islets and in vivo in human islets transplanted into high-fat diet-fed mice. Pharmacological inhibition of BMP signaling protects human β-cells from tacrolimus-induced β-cell dysfunction in vitro. Furthermore, we confirm that BMP/SMAD signaling is activated in protocol pancreas allograft biopsies from recipients on tacrolimus. To conclude, we propose a novel mechanism underlying the diabetogenicity of tacrolimus in primary human β-cells. This insight could lead to new treatment strategies for new-onset diabetes and may have implications for other forms of diabetes.
journal_name
Diabetesjournal_title
Diabetesauthors
Triñanes J,Ten Dijke P,Groen N,Hanegraaf M,Porrini E,Rodriguez-Rodriguez AE,Drachenberg C,Rabelink TJ,de Koning E,Carlotti F,de Vries APJdoi
10.2337/db19-0828subject
Has Abstractpub_date
2020-02-01 00:00:00pages
193-204issue
2eissn
0012-1797issn
1939-327Xpii
db19-0828journal_volume
69pub_type
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