Tacrolimus-Induced BMP/SMAD Signaling Associates With Metabolic Stress-Activated FOXO1 to Trigger beta-Cell Failure

Trinanes, J.; Dijke, P. ten; Groen, N.; Hanegraaf, M.; Porrini, E.; Rodriguez-Rodriguez, A.E.; ... ; Vries, A.P.J. de (2020)

Article / Letter to editor

Active maintenance of beta-cell identity through fine-tuned regulation of key transcription factors ensures beta-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 beta-cell maturity and beta-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 beta-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 beta-cells from tacrolimus-induced beta-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 beta-cells. This insight could lead to new treatment strategies for new-onset diabetes and may have implications for other forms of diabetes.

• All authors: Trinanes, J.; Dijke, P. ten; Groen, N.; Hanegraaf, M.; Porrini, E.; Rodriguez-Rodriguez, A.E.; Drachenberg, C.; Rabelink, T.J.; Koning, E. de; Carlotti, F.; Vries, A.P.J. de
• Date: 2020-02-01
• Journal: Diabetes
• Volume: 69
• Issue: 2
• Pages: 193 - 204
• DOI: doi:10.2337/db19-0828