Diazoxide-induced beta-cell rest reduces endoplasmic reticulum stress in lipotoxic beta-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 beta-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 beta-cells exposed to the fatty acid palmitate. The eukaryotic translation factor 2-alpha kinase 3 (EIF2AK3; also known as PERK) and endoplasmic reticulum to nucleus signaling 1 (ERN1; also known as IRE1) 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 ERN1 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.
Sargsyan
Ernest
E
Department of Medical Cell Biology, Uppsala University, SE-75123, Uppsala, Sweden.
Ortsäter
Henrik
H
Thorn
Kristofer
K
Bergsten
Peter
P
D051702:Activating Transcription Factor 6 / Q000378:metabolism; D017398:Alternative Splicing / Q000187:drug effects / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics; D003981:Diazoxide / Q000494:pharmacology*; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D004722:Endoribonucleases / Q000378:metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010168:Palmitates / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051742:Transcription Factor CHOP / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics; D019892:eIF-2 Kinase / Q000378:metabolism
D051702:Activating Transcription Factor 6; D004268:DNA-Binding Proteins; D003981:Diazoxide; D004722:Endoribonucleases; D015852:Eukaryotic Initiation Factor-2; D005947:Glucose; D007328:Insulin; D010168:Palmitates; D017346:Protein Serine-Threonine Kinases; D000071701:Regulatory Factor X Transcription Factors; D051742:Transcription Factor CHOP; D014157:Transcription Factors; D019892:eIF-2 Kinase; C497112:Atf6 protein, mouse; C497250:Ddit3 protein, mouse; C510185:Ern1 protein, mouse