Heparan sulfate (HS) is a linear polysaccharide and abundantly distributes around cell surface. HS can interact with various bioactive molecules and enhance their signal transduction. Thus, HS is involved in diverse biological functions including development, maturation and proliferation of various tissues. Previous reports demonstrated the expression of HS in β-cells and suggested the possible involvement of HS in functions of β-cells. However, the importance of HS for β-cells remains largely unknown. In the present study, we generated mice with β-cell specific deletion of Ext1 (cKO), which encodes an essential enzyme for HS synthesis, to investigate the detailed roles of HS in β-cell development and function. cKO mice had decreased body weight despite increased food intake compared to control mice. cKO mice showed impaired glucose tolerance associated with decreased insulin secretion upon glucose challenge, without insulin resistance. Glucose-induced insulin secretion from isolated islets of cKO mice was also significantly reduced. These results indicate the contribution of HS in β-cells to insulin secretion and glucose homeostasis. The expression of several genes essential for glucose-induced insulin secretion was decreased in cKO islets. Pdx1 and MafA, which are important transcriptional factors for β-cell development and maturation, were reduced in cKO islets, indicating HS promotes development and maturation of β-cells. Immunohistochemical analysis of the cKO pancreas revealed reduced β-cell mass and islet number. The percentage of BrdU- or Ki67-positive β-cells was decreased in cKO islets, suggesting the involvement of HS in the proliferation of β-cells. Insufficient vascularization in cKO islets might contribute to the abnormal islet architecture. These data demonstrate that HS plays diverse roles in β-cell development and maturation, and that loss of HS leads to insufficient insulin secretion and dysregulation of glucose homeostasis.
T. Matsuzawa: None. T. Yoshikawa: None. A. Sugawara: None. K. Yanai: None.