Asymmetric dimethylarginine accumulation under hyperglycemia facilitates 0-cell apoptosis via inhibiting nitric oxide production

Low concentrations of nitric oxide (NO) produced by constitutive NO synthase (cNOS) has been shown to suppress apoptosis in pancreatic 0-cells. In the present study, the influence of asymmetric dimethy-larginine (ADMA), the major endogenous inhibitor of NOS, on the apoptosis-suppressive effect of NO was investigated. The expression of dimethylarginine dimethylaminohydrolase 2 (DDAH2), an ADMA-metabolizing enzyme, in INS-1 0-cells and in mouse pancreatic islets was drastically reduced by in vitro exposure to high-concentration glucose (20 mM) and by in vivo treatment of mice with the insulin receptor blocker S661, which resulted in hyperglycemia, respectively. In line with this, a higher ADMA level was observed in INS-1 cells exposed to 20 mM glucose. The treatment of INS-1 cells with ADMA, similarly to with the NOS inhibitor NG-nitro-L-arginine methyl ester, significantly facilitated 20 mM glucose-induced increase in cleaved caspase-3 protein expression. Furthermore, increased pro-tein expression of cleaved caspase-3 and CHOP was observed in INS-1 cells with knockdown of DDAH2. These results suggest that ADMA accumulation through a decrease in DDAH2 expression in 0-cells, which is induced under hyperglycemic conditions, facilitates 0-cell apoptosis through suppression of cNOS-mediated NO production.(c) 2022 Elsevier Inc. All rights reserved.

Automated summary

This study found that high concentrations of glucose and the insulin receptor blocker S661 reduced the expression of DDAH2 in pancreatic β cells, leading to the accumulation of ADMA. The accumulation of ADMA suppressed the production of nitric oxide, resulting in increased apoptosis of pancreatic β cells.