Selenoprotein P (SeP; encoded by SELENOP) is a selenium (Se)-rich plasma protein and is synthesized mainly by the liver. SeP functions as a Se-supply protein to maintain antioxidative selenoprotein levels in peripheral tissue. Thus, SeP plays an essential role in the antioxidative defence. On the other hand, SeP is identified as a hepatokine, promoting insulin resistance in type 2 diabetes. SeP is upregulated in the liver of type 2 diabetes patients, and high levels of SeP impair insulin signaling and exercise resistance (Cell Metabolism 2010, Nature Med 2017). We also found that excess SeP decreased in pancreas insulin levels and high glucose-induced insulin secretion (Nature Commun 2017). Immunohistochemical analysis of pancreatic islets showed a reduction of the size of the islets in SeP-treated mice. Further, the islets of SeP-treated mice showed a disturbed morphology with irregular shape and a concomitant decrease of α cells with β cells. We identified anti-SeP antibody AE2 as neutralizing antibody with activity against Se-supply of SeP. Administration of AE2 significantly improved insulin levels and high glucose-induced insulin secretion in vitro and in vivo. These results suggest the critical role of SeP levels in function of pancreatic beta cells.