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β-cell-protective effect of 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH) as a glutamate dehydrogenase (GDH) activator in db/db mice

Other Titles
 db/ db 마우스에서 glutamate dehydrogenase (GDH) 활성제인 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH)의 베타세포 보호효과 
Issue Date
2012
Description
Dept. of Medicine/박사
Abstract
2-Aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH) is an activator of glutamate dehydrogenase (GDH), which is a mitochondrial enzyme with an important role in insulin secretion. We investigated the effect of BCH on the high glucose (HG)-induced reduction in glucose-stimulated insulin secretion (GSIS), the high glucose/palmitate (HG/PA)-induced reduction in insulin gene expression, and HG/PA-induced β-cell death. We also studied whether long-term treatment with BCH lowers blood glucose and improves β-cell integrity in db/db mice. We evaluated GSIS, insulin gene expression, and DNA fragmentation in INS-1 cells exposed to HG or HG/PA in the presence or absence of BCH. An in vivo study was performed, in which seven-week-old diabetic db/db mice were treated with BCH (0.7g/kg, n = 10) and with placebo (n = 10) every other day for 6 weeks. After treatment, an intraperitoneal glucose tolerance test and immunohistologic examinations were performed.Treatment with BCH blocked HG-induced GSIS inhibition and the HG/PA-induced reduction in insulin gene expression in INS-1 cells. In addition, BCH significantly reduced HG/PA-induced INS-1 cell death and phospho-JNK expression. BCH treatment improved glucose tolerance and insulin secretion in db/db mice. BCH treatment also increased the ratio of insulin-positive β-cells to total islet area (p < 0.05) and reduced the percentage of β-cells expressing cleaved caspase 3 (p < 0.05). In conclusion, the GDH activator BCH improved glycemic control in db/db mice. This anti-diabetic effect may be associated with improved insulin secretion, preserved islet architecture, and reduced β-cell apoptosis.
URI
http://ir.ymlib.yonsei.ac.kr/handle/22282913/133892
Appears in Collections:
2. 학위논문 > 1. College of Medicine (의과대학) > 박사
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