title: β-Cell-protective effect of 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid as a glutamate dehydrogenase activator in db/db mice.
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.
authors: Department of Endocrinology and Metabolism, Ajou University School of Medicine, San 5, Wonchon-dong, Yeongtong-gu, Suwon 443-721, South Korea.
authors: Seung Jin
authors: SJ
authors: Han
authors: Sung-E
authors: SE
authors: Choi
authors: Sang-A
authors: SA
authors: Yi
authors: Soo-Jin
authors: SJ
authors: Lee
authors: Hae Jin
authors: HJ
authors: Kim
authors: Dae Jung
authors: DJ
authors: Kim
authors: Hyun Chul
authors: HC
authors: Lee
authors: Kwan Woo
authors: KW
authors: Lee
authors: Yup
authors: Y
authors: Kang
mesh_terms: D000598:Amino Acids, Cyclic / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001786:Blood Glucose / Q000032:analysis; D045744:Cell Line, Tumor; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000503:physiopathology*; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D005969:Glutamate Dehydrogenase / Q000502:physiology*; D007328:Insulin / Q000097:blood / Q000235:genetics / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000502:physiology*; D007340:Insulinoma; D051379:Mice; D010190:Pancreatic Neoplasms; D051381:Rats
chemical_list: D000598:Amino Acids, Cyclic; D001786:Blood Glucose; D007328:Insulin; C006504:2-aminobicyclo(2,2,1)heptane-2-carboxylic acid; D005969:Glutamate Dehydrogenase; D005947:Glucose