Obesity-Induced Regulator of Calcineurin 1 Overexpression Leads to β-Cell Failure Through Mitophagy Pathway Inhibition

Aims: Type 2 diabetes (T2D) is associated with pancreatic β-cell dysfunction, manifested by reduced glucose-stimulated insulin secretion (GSIS). The regulator of calcineurin 1 (RCAN1) in islets is an endogenous inhibitor of calcium-activated protein phosphatase. Previous studies have indicated that global RCAN1 overexpression under high nutrient stress is involved in insulin resistance in T2D. However, the specific role and mechanism of this gene's overexpression in pancreatic β-cells have not been thoroughly elucidated to date. Results: In this study, we showed that mice overexpressing islet-specific RCAN1 exhibited a prediabetic phenotype with markedly reduced GSIS under nutrient stress. Overexpression of RCAN1 increased the autophagy-associated DNA methylation level of Beclin-1 suppressing the induction of autophagy, affected the protein kinase B, and downregulated the activation of mammalian target of rapamycin, leading to Miro1-mediated mitophagy deficiency. Furthermore, the exacerbated impairment of autophagy induction and mitophagy flux failures induced β-cell apoptosis, resulting in GSIS impairment, lipid imbalance, and NOD-like receptor 3 proinflammation under high nutrient stress in mice. Innovation: Our present data identify a detrimental effect of RCAN1 overexpression on Miro1-mediated mitophagy deficiency and β-cell dysfunction in high-fat diet-fed RCAN1 overexpressing mice. Conclusion: Our results revealed that strategies targeting RCAN1 in vivo may provide a therapeutic target to enhance β-cell mitophagy quality and may determine the crucial factor in T2D development.