Inhibitory effects of KHG26377 on glutamate dehydrogenase activity in cultured islets

Abstract

GDH has been known to be related with hyperinsulinismhyperammonemia syndrome. We have screened new drugs with a view to developing effective drugs modulating GDH activity. In the present work, we investigated the effects of a new drug, KHG26377 on glutamate formation and GDH activity in cultured rat islets. When KHG26377 was added to the culture medium for 24 h prior to kinetic analysis, the Vmax of GDH was decreased by 59% whereas Km is not significantly changed. The concentration of glutamate decreased by 50% and perfusion of islets with KHG26377 reduced insulin release by up to 55%. Our results show that KHG26377 regulates insulin release by inhibiting GDH activity in primary cultured islets and support the previous studies for the connection between GDH activity and insulin release. Further studies are required to determine in vivo effects and pharmacokinetics of the drug. [BMB reports 2010; 43(4): 245-249]

Inhibition of glutamate dehydrogenase and insulin secretion by KHG26377 does not involve ADP-ribosylation by SIRT4 or deacetylation by SIRT3

“…Green tea polyphenols inhibit GDH and reduce insulin release when pancreatic islets are stimulated with glutamine and BCH (2-amino-2-norbornane carboxylic acid), although not upon glucose stimulation (12). We previously reported the loss of GDH activity following perfusion of islets with KHG26377, a thiazole derivative, in vitro (22). KHG26377 also reduced the amount of insulin released and caused a rightward shift in the concentration dependence of glucose-induced insulin secretion in islets (22).…”

“…The N-and C-terminal regions of SIRT3 influence its activity against GDH and peptide substrates, indicating that these regions play roles in regulation and substrate recognition (21). Our recent study showed that KHG26377 (2-cyclopropylimino-3-methyl-1,3-thiazoline hydrochloride) inhibits GDH activity and downregulates insulin secretion in pancreatic islets (22). However, its mechanisms of action have not yet been elucidated.…”

“…We previously reported the loss of GDH activity following perfusion of islets with KHG26377, a thiazole derivative, in vitro (22). KHG26377 also reduced the amount of insulin released and caused a rightward shift in the concentration dependence of glucose-induced insulin secretion in islets (22). To further investigate the mechanism and effects of KHG26377 on GDH activity and insulin secretion in vivo, we injected mice intraperitoneally with different concentrations of KHG26377.…”

“…A number of recent studies have used inhibitors to decrease GDH activity in pancreatic islets (7,12,(22)(23)(24)(25)(26). Upon glucose stimulation, GDH inhibition results in both diminished insulin release and decreased cellular glutamate levels (26).…”

2-Amino-1,3-thiazoles Suppressed Lipopolysaccharide-Induced IL-β and TNF-α

“…We previously reported that 2-cyclopropylimino-3-methyl-1,3-thiazoline hydrochloride suppressed glutamate-induced excitotoxicity in rat glial cultures 5 and inhibited glutamate dehydrogenase activity in cultured islets. 6 As an extension of our efforts to investigate the biological activities of the analogues, we report here that 2-aminothiazole derivatives effectively suppress the lipopolysaccharide (LPS)-induced interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) level.…”