Exposure to chronic high glucose induces beta-cell apoptosis through decreased interaction of glucokinase with mitochondria: downregulation of glucokinase in pancreatic beta-cells.
Chronic hyperglycemia is toxic to pancreatic beta-cells, impairing cellular functioning as observed in type 2 diabetes; however, the mechanism underlying beta-cell dysfunction and the resulting apoptosis via glucose toxicity are not fully characterized. Here, using MIN6N8 cells, a mouse pancreatic beta-cell line, we show that chronic exposure to high glucose increases cell death mediated by Bax oligomerization, cytochrome C release, and caspase-3 activation. During apoptosis, glucokinase (GCK) expression decreases in high-glucose-treated cells, concomitant with a decrease in cellular ATP production and insulin secretion. Moreover, exposure to a chronically high dose of glucose decreases interactions between GCK and mitochondria with an increase in Bax binding to mitochondria and cytochrome C release. These events are prevented by GCK overexpression, and phosphorylation of proapoptotic Bad proteins in GCK-overexpressing cells is prolonged compared with Neo-transfected cells. Similar results are obtained using primary islet cells. Collectively, these data demonstrate that beta-cell apoptosis from exposure to chronic high glucose occurs in relation to lowered GCK expression and reduced association with mitochondria. Our results show that this may be one mechanism by which glucose is toxic to beta-cells and suggests a novel approach to prevent and treat diabetes by manipulating Bax- and GCK-controlled signaling to promote apoptosis or proliferation.
Kim
Won-Ho
WH
Division of Metabolic Disease, Department of Biomedical Science, National Institutes of Health, #5 Nokbun-dong, Eunpyung-gu, Seoul 122-701, South Korea.
Lee
June Woo
JW
Suh
Young Ho
YH
Hong
Shin Hee
SH
Choi
Joo Sun
JS
Lim
Joo Hyun
JH
Song
Ji Hyun
JH
Gao
Bin
B
Jung
Myeong Ho
MH
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000502:physiology; D015536:Down-Regulation; D005941:Glucokinase / Q000378:metabolism*; D005947:Glucose / Q000502:physiology*; D007515:Islets of Langerhans / Q000502:physiology*; D008928:Mitochondria / Q000502:physiology*; D013997:Time Factors
D045304:Cytochromes c; D005941:Glucokinase; D005947:Glucose