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

Area of Science:

• Endocrinology
• Immunology
• Molecular Biology

Background:

• Maintaining beta-cell identity is crucial for insulin secretion and diabetes prevention.
• Tacrolimus (immunosuppressant) is linked to increased diabetes risk post-transplant, but mechanisms are unknown.
• Beta-cell dysfunction underlies various forms of diabetes.

Purpose of the Study:

• To elucidate the molecular mechanisms by which tacrolimus induces beta-cell dysfunction and failure.
• To investigate the role of the BMP/SMAD signaling pathway in tacrolimus-induced diabetogenicity.
• To explore potential therapeutic strategies targeting this pathway.

Main Methods:

• In vitro studies using primary human islets and in vivo studies with human islets transplanted into mice.
• Analysis of beta-cell maturity, insulin secretion, and key transcription factor expression (MAFA).
• Investigation of the BMP/SMAD signaling pathway activation and its interaction with FOXO1 under metabolic stress.

Main Results:

• Tacrolimus induces loss of human beta-cell maturity and function, particularly under mild metabolic stress.
• Tacrolimus activates BMP/SMAD signaling, leading to phosphorylated SMAD1/5.
• This activation synergizes with metabolic stress-activated FOXO1, reducing MAFA expression and abolishing insulin secretion.
• BMP signaling inhibition protected beta-cells from tacrolimus-induced dysfunction.
• Activated BMP/SMAD signaling was confirmed in pancreas allograft biopsies from tacrolimus recipients.

Conclusions:

• Tacrolimus promotes human beta-cell failure via BMP/SMAD pathway activation, especially under metabolic stress.
• This mechanism involves the interaction of tacrolimus-induced pSMAD1/5 with FOXO1, impairing MAFA expression and insulin secretion.
• Targeting BMP signaling may offer novel therapeutic approaches for tacrolimus-induced diabetes and potentially other forms of diabetes.