IPO13 sustains glucose homeostasis by regulating glucose stimulated insulin secretion through Foxo1/Txnip pathway in health and diabetes

Defects in glucose-stimulated insulin secretion (GSIS) underlie diabetes pathogenesis. Although key beta-cell transcription factors regulate GSIS, the mechanisms governing their nucleocytoplasmic shuttling and function remain poorly understood. We demonstrated that beta-cell-specific deletion of importin 13 impeded Foxo1 nuclear localization, leading to upregulated thioredoxin-interacting protein (Txnip), impaired GSIS, and early-onset diabetes. Notably, IPO13 exhibited biphasic responses to glucose, and its deficiency was evident in islets exposed to chronic high glucose, islets of high-fat-diet-fed mice, and islets of patients with type 2 diabetes. Restoring IPO13 expression fully rescued GSIS impairment in IPO13-deficient islets. Importantly, an IPO13 mutation (IPO13-R803Q) was identified in a family with early-onset diabetes. Multiple independent experiments demonstrated that IPO13 wild-type, but not R803Q, interacted and regulated Foxo1 nuclear transport, through which downregulated Txnip, restored GSIS, and alleviated diabetes in IPO13-beta KO mice. These findings establish IPO13 acting as a sensor and effector regulating beta-cell function in health and diabetes.