1745-P: IPO13 Maintains Glucose Homeostasis by Regulating Insulin Secretion and α-Cell Expansion

Introduction & Objective: Importin 13 (IPO13) is a member of IPOβ family and is one of only three mammalian IPO proteins able to mediate both import and export of cargo proteins. IPO13 contributes to brain and eye development, however the role of IPO13 in β cell function and glucose homeostasis remains unknown. Herein, we performed a new β cell-specific IPO13 knockout (IPO13-βKO) mouse model to investigate the β cell function changes caused by IPO13 deficiency.

Methods: Body weight, fasting blood glucose, and plasma insulin levels was tested weekly to observe the glucose homeostasis of IPO13-βKO mice. Insulin or glucagon gene expression, proinsulin processing, and insulin or glucagon content were detected. Isolated islets insulin and glucagon secretion ability was measured by glucose-stimulated insulin secretion test. Transcriptome analysis of associated genes GO term were used to understand the related gene changes.

Results: IPO13 was downregulated in β cells of diabetic db/db mice and high-fat fed mice, revealing a possible role of IPO13 in β-cell function. IPO13-βKO caused severe early-onset, insulin-deficient diabetes. Functional studies revealed the decreased expression of prohormone convertase 1/3 and carboxypeptidase E, and increased abnormal insulin granules, resulting in the decreased insulin production. Islet transcriptome analysis showed decreased expression of genes associated with β-cell maturation. Multiple experiments confirmed that, although IPO13 deletion decreased insulin, the expansion of α cells and elevated glucagon levels, especially after glucose stimulation. Importantly, IPO13 deficiency decreased expression of β-cell function-related genes, including Glut2, Cask, and Syt7, contributing to impaired islet glucose-stimulated insulin secretion (GSIS).

Conclusion: Our study not only reveal a critical role of IPO13 in the regulation of insulin secretion and α cell expansion but also provide insight into the mechanism of diabetes caused by IPO13 deficiency.