Diazoxide-induced β-cell rest reduces endoplasmic reticulum stress in lipotoxic β-cells

Elevated levels of glucose and lipids are characteristics of individuals with type 2 diabetes mellitus (T2DM). The enhanced nutrient levels have been connected with deterioration of beta-cell function and impaired insulin secretion observed in these individuals. A strategy to improve P-cell function in individuals with T2DM has been intermittent administration of K-ATP channel openers. After such treatment, both the magnitude and kinetics of insulin secretion are markedly improved. In an attempt to further delineate mechanisms of how openers of K-ATP, channels improve beta-cell function, the effects of diazoxide on markers of endoplasmic reticulum (ER) stress was determined in P-cells exposed to the fatty acid palmitate. The eukaryotic translation factor 2-alpha kinase 3 (EIF2AK3; also known as PEPK) and endoplasmic reticulum to nucleus signaling 1 (ERNI; also known as IR-E1) pathways, but not the activating transcription factor (ATF6) pathway of the unfolded protein response, are activated in such lipotoxic beta-cells. Inclusion of diazoxide during culture attenuated activation of the EIF2AK3 pathway but not the EPN1 pathway. This attenuation was associated with reduced levels of DNA-damage inducible transcript 3 (DDIT3; also known as CHOP) and beta-cell apoptosis was decreased. It is concluded that reduction of ER stress may be a mechanism by which diazoxide improves beta-cell function.