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E Sargsyan, Department of Medical Cell Biology, Uppsala university, Uppsala, Sweden
H Ortsater, Department of Clinical Science and Education, Karolinska Institute, Stockholm, Sweden
K Thorn, Department of Medical Cell Biology, Uppsala university, Uppsala, Sweden
P Bergsten, Department of Medical Cell Biology, Uppsala university, Uppsala, 75123, Sweden

Correspondence: Peter Bergsten, Email: Peter.Bergsten{at}mcb.uu.se

Abstract

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 beta-cell function in persons with T2DM has been intermittent administration of KATP channel openers. After such treatment both the magnitude and kinetics of insulin secretion is markedly improved. In an attempt to further delineate mechanisms of how openers of KATP channels improve beta-cell function, the effects of diazoxide on markers of endoplasmic reticulum (ER) stress was determined in beta-cells exposed to the fatty acid palmitate. The PERK and IRE1 pathways but not the ATF6 pathway of the unfolded protein response (UPR) are activated in such lipotoxic beta-cells. Inclusion of diazoxide during culture attenuated activation of the PERK but not the IRE1 pathway. This attenuation was associated with reduced levels of 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.

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