Evidence showed strong relations between malondialdehyde (MDA) levels and different pathological stages of diabetes. Here, an explicit system with freshly isolated islets and precisely controlled MDA gradient was employed to investigate the physiological effect of MDA on GSIS. Promoter analysis, pathway mapping, Q-PCR profiling, and siRNA verification were performed to clarify the intracellular signaling pathways. MDA at a moderately high level (5 and 10μM) promoted GSIS and accompanied with ATP/ADP ratio, cytosolic Ca(2+) level, and key regulators (GK, GLUT2, PDX1, and UCP2) changes in islets. Both upstream (PI3K and p-AKT) and downstream (TCF7L2 and TCF7) factors of Wnt pathway showed greatest changes. Knockdown of TCF7L2 blocked the MDA-induced GSIS elevation. These results indicated that MDA acted as a signaling messenger and regulated islet GSIS mainly through Wnt pathway. Therefore, the elevated MDA level and up-regulated Wnt signaling pathway could be an etiological factor in the development of hyperinsulinemia and type 2 diabetes.
Keywords: Diabetes; Glucose-stimulated insulin secretion; Hyperinsulinemia; Malondialdehyde; TCF7L2; Wnt signaling pathway.
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