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Diabetes 54:2602-2611, 2005
© 2005 by the American Diabetes Association, Inc.
Exposure to Chronic High Glucose Induces ß-Cell Apoptosis Through Decreased Interaction of Glucokinase With Mitochondria
Downregulation of Glucokinase in Pancreatic ß-Cells
1 Division of Metabolic Disease, Department of Biomedical Science, National Institutes of Health, Seoul, South Korea
2 Division of Optical Metrology, Korea Research Institute of Standards and Science, Yuseong, South Korea
3 Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
Chronic hyperglycemia is toxic to pancreatic ß-cells, impairing cellular functioning as observed in type 2 diabetes; however, the mechanism underlying ß-cell dysfunction and the resulting apoptosis via glucose toxicity are not fully characterized. Here, using MIN6N8 cells, a mouse pancreatic ß-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 ß-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 ß-cells and suggests a novel approach to prevent and treat diabetes by manipulating Bax- and GCK-controlled signaling to promote apoptosis or proliferation.
Address correspondence and reprint requests to Dr. Myeong Ho Jung, Division of Metabolic Disease, Department of Biomedical Science, National Institutes of Health, #5 Nokbun-dong, Eunpyung-gu, Seoul 122-701, South Korea. E-mail: jung0603{at}nih.go.kr
Abbreviations: FITC, fluorescein isothiocyanate; GCK, glucokinase; GFP, green fluorescent protein; GST, glutathione S-transferase; KRBB, Krebs-Ringer bicarbonate buffer; PARP, poly(ADP-ribose) polymerase; ROS, reactive oxygen species; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling; VDAC, voltage-dependent anion channel
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