Involvement of exogenous 3-deoxyglucosone in β-cell dysfunction induces impaired glucose regulation

Abstract

β-cell dysfunction is the primary cause of type 2 diabetes mellitus (T2DM). 1, 2-dicarbonyl compounds, such as 3-deoxyglucosone (3DG) have been reported to increase the risk of T2DM. Abnormal elevation of plasma 3DG may impair β-cell function and thereby, it is linked to T2DM. Previous findings suggest that exogenous 3DG may serve an important role in the development of pre-diabetes. In the present study, the authors examine whether exogenous 3DG induces impaired glucose regulation in mice by decreasing β-cell function involving of accumulation of plasma 3DG. At two weeks following administration of 3DG, fasting blood glucose (FBG) levels, oral glucose tolerance (by a glucose meter) and plasma levels of 3DG (by HPLC) and insulin (by radioimmunoassay) were measured. Glucose-stimulated insulin secretion in cultured pancreas islets and INS-1 cells was measured by radioimmunoassay. Western blotting was used to examine the expression of the key molecules of the insulin-PI3K signaling pathway. 3DG treatment increased FBG and fasting blood insulin levels, reduced oral glucose tolerance in conjunction with decreased ΔIns30-0/ΔG30-0. In 3DG-treated mice, an increase in the plasma 3DG level was observed, which was most likely the mechanism for decreased β-cell function. This idea was further supported by these results that non-cytotoxic 3DG concentration obviously decreased glucose-stimulated insulin secretion in cultured pancreas islets and INS-1 cells exposure to high glucose (25.5 mM). 3DG decreased the expression of GLUT2 and phosphorylation of IRS-1, PI3K-p85 and Akt in high glucose-induced INS-1 cells. To the best of the authors' knowledge, the present study is the first to demonstrate that exogenous 3DG induced normal mice to develop IGR, resulting from β-cell dysfunction. Exogenous 3DG administration increased plasma 3DG levels, which participates in inducing β-cell dysfunction, at least in part, through impairing IRS-1/PI3K/GLUT2 signaling.