The Effects of Antidiabetic Drugs on Cerebral Metabolism in Mice with Central Insulin Resistance

Abstract

Objectives: This study focused on the effects of antidiabetic drugs, alogliptin (Nesina), exenatide (Byetta) and pioglitazone (Actos), on astrocyte-neuron metabolic cooperation in mice with central insulin resistance. That may provide theoretical basis for clinical treatment of diabetes related cognitive dysfunction. Methods: Male C57BL/6J mice were randomly divided into control group (Ctrl), high-fat group (HF), alogliptin (ALO) group, exenatide (EXE) group and pioglitazone (PIO) group. Ctrl group was served normal diet, and then the others were served high-fat diet for 12 weeks. Then ALO group, EXE group and PIO group were respectively treated with alogliptin (25mg/kg/day), exenatide (30ug/kg/day) and pioglitazone (10mg/kg/day) for 4 weeks. The memory was tested using the Morris Water Maze test after 16 weeks. Then mice were killed and the brains were removed to detect insulin signaling and metabolic parameters. All data were presented as mean±SD and P<0.05 was considered statistically different. Results: 1. Antidiabetic drugs improved insulin signaling, IRS1/PI3K/Akt pathway in hippocampus and cortex. 2. Comparative analysis indicated that the latency in finding the platform significantly decreased, while frequency of crossing platform were increased in ALO group (3.75±1.14), EXE group (3.33±1.07) and PIO group (4.00±1.71) compared to HF group (1.66±1.23) (P<0.05). 3. The results showed that the expression of glucose transporter (GLUT) 1, GLUT3, monocarboxylate transporter (MCT)1, MCT2 and MCT4 in HF group were significantly lower than those in Ctrl group, no matter in hippocampus and cortex. ALO group, EXE group and PIO group obviously reversed metabolic parameters compared to HF group. Conclusions: We demonstrated that reprogramming metabolic pathways is an elaborate way by which neural cells respond to central insulin resistance. And antidiabetic drugs can reverse metabolic pathways to protect memory. Disclosure Y. Cao: None. G. Wang: None. Z. Li: None.