G6PD up-regulation promotes pancreatic beta-cell dysfunction.
Increased reactive oxygen species (ROS) induce pancreatic β-cell dysfunction during progressive type 2 diabetes. Glucose-6-phosphate dehydrogenase (G6PD) is a reduced nicotinamide adenine dinucleotide phosphate-producing enzyme that plays a key role in cellular reduction/oxidation regulation. We have investigated whether variations in G6PD contribute to β-cell dysfunction through regulation of ROS accumulation and β-cell gene expression. When the level of G6PD expression in pancreatic islets was examined in several diabetic animal models, such as db/db mice and OLEFT rats, G6PD expression was evidently up-regulated in pancreatic islets in diabetic animals. To investigate the effect of G6PD on β-cell dysfunction, we assessed the levels of cellular ROS, glucose-stimulated insulin secretion and β-cell apoptosis in G6PD-overexpressing pancreatic β-cells. In INS-1 cells, G6PD overexpression augmented ROS accumulation associated with increased expression of prooxidative enzymes, such as inducible nitric oxide synthase and reduced nicotinamide adenine dinucleotide phosphate oxidase. G6PD up-regulation also caused decrease in glucose-stimulated insulin secretion in INS-1 cells and primary pancreatic islets. Moreover, elevated G6PD expression led to β-cell apoptosis, concomitant with the increase in proapoptotic gene expression. On the contrary, suppression of G6PD with small interference RNA attenuated palmitate-induced β-cell apoptosis. Together, these data suggest that up-regulation of G6PD in pancreatic β-cells would induce β-cell dysregulation through ROS accumulation in the development of type 2 diabetes.
Department of Biological Sciences, Seoul National University, San 56-1, Sillim-Dong, Kwanak-Gu, Seoul 151-742, Korea.
Joo-Won
JW
Lee
A Hyun
AH
Choi
Mira
M
Ham
Ji-Won
JW
Kim
Sung Sik
SS
Choe
Jiyoung
J
Park
Gha Young
GY
Lee
Kun-Ho
KH
Yoon
Jae Bum
JB
Kim
D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D005947:Glucose; D005954:Glucosephosphate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D010168:Palmitates; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species; D015854:Up-Regulation
D007328:Insulin; D010168:Palmitates; D017382:Reactive Oxygen Species; D005954:Glucosephosphate Dehydrogenase; D005947:Glucose