Tacrolimus- and sirolimus-induced human β cell dysfunction is reversible and preventable.

Area of Science:

• Endocrinology
• Immunology
• Transplantation Biology

Background:

• Posttransplantation diabetes mellitus (PTDM) is a significant complication following organ or cell transplantation.
• Immunosuppressive agents, such as calcineurin inhibitors (tacrolimus) and mTOR inhibitors (sirolimus), are crucial for preventing transplant rejection but can induce PTDM.

Purpose of the Study:

• To investigate the effects of tacrolimus (TAC) and sirolimus (SIR) on human islet function in vivo.
• To determine if these drug-induced effects are reversible or preventable.

Main Methods:

• Human islets were transplanted into immunodeficient mice and treated with clinically relevant levels of TAC or SIR.
• Insulin secretion, islet amyloid deposition, macrophage infiltration, insulin granule formation, and gene expression were analyzed.
• Reversibility and prevention strategies using a GLP-1 receptor agonist were explored.

Main Results:

• Both TAC and SIR impaired insulin secretion under various conditions.
• Drug treatment increased islet amyloid deposition and macrophages, disrupted insulin granule formation, and caused transcriptional dysregulation.
• These detrimental effects on beta cells reversed upon drug withdrawal.
• GLP-1 receptor agonist co-treatment prevented TAC-induced dysfunction and partially prevented SIR-induced dysfunction.

Conclusions:

• Calcineurin and mTOR signaling pathways are critical for human beta cell function in vivo.
• Modulating these pathways holds potential for preventing or ameliorating PTDM.