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Wfs1 is an endoplasmic reticulum (ER) membrane located protein highly expressed in pancreatic β cells and brain. Wfs1 deficiency causes adult pancreatic β cells dysfunction following β cells apoptosis. Previous studies mainly focus on the Wfs1 function in adult mouse pancreatic β cells. However, whether Wfs1 loss-of-function impairs mouse pancreatic β cell from its early development is unknown. In our study, Wfs1 deficiency disrupts the composition of mouse pancreatic endocrine cells from early postnatal day 0 (P0) to 8 weeks old, with decreased percentage of β cells and increased percentage of α and δ cells. Meanwhile, Wfs1 loss-of-function leads to reduced intracellular insulin content. Notably, Wfs1 deficiency impairs Glut2 localization and causes the accumulation of Glut2 in mouse pancreatic β cell cytoplasm. In Wfs1 -deficient mice, glucose homeostasis is disturbed from early 3 weeks old to 8 weeks old. This work reveals that Wfs1 is significantly required for the composition of pancreatic endocrine cells and is essential for Glut2 localization in mouse pancreatic β cells. • Wfs1 deficiency disrupts the composition of mouse pancreatic endocrine cells from P0 to 8 weeks old. • Wfs1 deficiency causes the reduction of intracellular insulin content. • Wfs1 loss-of-function impairs Glut2 localization to cytomembrane. • Wfs1 -deficient mice show disturbances in glucose tolerance from 3 weeks old. [ABSTRACT FROM AUTHOR]