GLP-1 ameliorates the proliferation activity of INS-1 cells inhibited by intermittent high glucose concentrations through the regulation of cyclins

Glucagon-like peptide-1 (GLP-1) and its analog exendin (EX)-4 have been considered to promote beta-cell growth and expansion. In the present, study we investigated the effect of GLP-1 on proliferative activity and cell cycle regulation in the pancreatic insulin-secreting beta-cell line, INS-1, treated with intermittent high glucose. INS-1 cells were treated with normal glucose (5.5 mmol/l), constant high glucose (30 mmol/l) and intermittent high glucose (rotation/24 h in 5.5 or 30 mmol/l) in the presence or absence of GLP-1 (100 nmol/l) for seven days. Proliferative activity, cell cycle and the expression of cyclin D1, p21, p27 and Skp2 were examined. INS-1 treated with intermittent high glucose and GLP-1 demonstrated a significant increase in proliferation activity (1.45 +/- 0.12; P<0.01) and decreased cell proportion in G0/G1 phase (49.73 +/- 4.04%,.P<0.01) compared with those without GLP-1. Furthermore, the expression levels of cyclin D1 and Skp2 were increased, while the expression of p27 and p21 were significantly reduced. Similar results were identified in those treated with constant high glucose and GLP-1. These results suggest that GLP-1 may ease the G0-G1 cell cycle arrest of INS-1 cells induced by intermittent high glucose by upregulating the expression of cyclin D1 and Skp2, downregulating the expression of p21 and p27, and finally promoting the cell cycle progression and proliferation activity.