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 highglucose (HG)-induced reduction in glucose-stimulated insulin secretion (GSIS), the HG/palmitate (PA)-induced reduction in insulin gene expression, and HG/PA-induced b-cell death. We also studied whether long-term treatment with BCH lowers blood glucose and improves b-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, nZ10) and placebo (nZ10) 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 b-cells to total islet area (P!0 . 05) and reduced the percentage of b-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 b-cell apoptosis.

Acute hypoxia induces apoptosis of pancreatic β-cell by activation of the unfolded protein response and upregulation of CHOP

“…27, 28 However, the state of oxygen availability in the islets of these animals has not been previously investigated. We have therefore assessed the potential hypoxic status of these islets by evaluating the formation of pimanidazole adducts.…”

“…27, 28 Also UPR components such as Bip and XBP-1 and the pro-apoptotic transcription factor CHOP have been shown to be upregulated in db/db pancreatic islets. 35, 36 Furthermore, an increase in CHOP protein has been observed in human islets of diabetic patients.…”

Hypoxia induces a HIF-1α dependent signaling cascade to make a complex metabolic switch in SGBS-adipocytes

“…In β-cells, an overexpression of GLUD is known to result in an enhanced glutamate oxidation and insulin secretion (Carobbio et al, 2004), improving glucose tolerance in vivo (Han et al, 2012). In hypoxic SGBS adipocytes, we assessed on the one hand elevated glutathione levels and on the other hand impaired GLUD mRNA levels.…”

Geniposide promotes beta-cell regeneration and survival through regulating β-catenin/TCF7L2 pathway

“…Various reagents that increase plasma insulin levels and exert hypoglycemic effects in db/db mice have been reported. 27 , 28 , 29 Here we noticed that geniposide significantly elevated insulin levels in diabetic mice compared with the levels in vehicle-treated diabetic mice (2.2-fold and 1.6-fold higher than corresponding vehicle-treated controls in HFD and db/db mice, respectively; Figure 4e ). Immunostaining for β -cells showed reduced β -cell mass ( Figure 4f ) and deteriorated islet morphology ( Figure 5a ) in the vehicle-treated HFD and db/db mice.…”