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

Authors
Han, SJ; Choi, SE; Yi, SA; Lee, SJ; Kim, HJ; Kim, DJ; Lee, HC; Lee, KW; Kang, Y
Citation
The Journal of endocrinology, 212(3):307-315, 2012
Journal Title
The Journal of endocrinology
ISSN
0022-07951479-6805
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 HG/palmitate (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 7-week-old diabetic db/db mice were treated with BCH (0.7  g/kg, n = 10) and placebo (n = 10) every other day for 6 weeks. After treatment, an intraperitoneal glucose tolerance test and immunohistological 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 level. 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.
MeSH terms
Amino Acids, Cyclic/*pharmacologyAnimalsApoptosis/drug effectsBlood Glucose/analysisDiabetes Mellitus/drug therapy/*physiopathologyDrug SynergismEnzyme Activation/drug effectsGene Expression/drug effectsGlucose/pharmacologyGlutamate Dehydrogenase/*physiologyInsulin/blood/genetics/secretionInsulin-Secreting Cells/*drug effects/*physiologyInsulinomaMicePancreatic NeoplasmsRats
DOI
10.1530/JOE-11-0340
PMID
22131441
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Endocrinology & Metabolism
Journal Papers > School of Medicine / Graduate School of Medicine > Physiology
AJOU Authors
한, 승진김, 혜진김, 대중이, 관우강, 엽
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