Chronic hyperglycemia is toxic to pancreatic ␤-cells, impairing cellular functioning as observed in type 2 diabetes; however, the mechanism underlying ␤-cell dysfunction and the resulting apoptosis via glucose toxicity are not fully characterized. Here, using MIN6N8 cells, a mouse pancreatic ␤-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 ␤-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 ␤-cells and suggests a novel approach to prevent and treat diabetes by manipulating Bax-and GCK-controlled signaling to promote apoptosis or proliferation. Diabetes 54:2602-2611, 2005

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Insulin resistance occurs early in the disease process, preceding the development of type 2 diabetes. Therefore, the identification of molecules that contribute to insulin resistance and leading up to type 2 diabetes is important to elucidate the molecular pathogenesis of the disease. To this end, we characterized gene expression profiles from insulin-sensitive tissues, including adipose tissue, skeletal muscle, and liver tissue of Zucker diabetic fatty (ZDF) rats, a well characterized type 2 diabetes animal model. Gene expression profiles from ZDF rats at 6 weeks (pre-diabetes), 12 weeks (diabetes), and 20 weeks (late-stage diabetes) were compared with age-and sex-matched Zucker lean control (ZLC) rats using 5000 cDNA chips. Differentially regulated genes demonstrating.1·3-fold change at age were identified and categorized through hierarchical clustering analysis. Our results showed that while expression of lipolytic genes was elevated in adipose tissue of diabetic ZDF rats at 12 weeks of age, expression of lipogenic genes was decreased in liver but increased in skeletal muscle of 12 week old diabetic ZDF rats.These results suggest that impairment of hepatic lipogenesis accompanied with the reduced lipogenesis of adipose tissue may contribute to development of diabetes in ZDF rats by increasing lipogenesis in skeletal muscle. Moreover, expression of antioxidant defense genes was decreased in the liver of 12-week old diabetic ZDF rats as well as in the adipose tissue of ZDF rats both at 6 and 12 weeks of age. Cytochrome P450 (CYP) genes were also significantly reduced in 12 week old diabetic liver of ZDF rats. Genes involved in glucose utilization were downregulated in skeletal muscle of diabetic ZDF rats, and the hepatic gluconeogenic gene was upregulated in diabetic ZDF rats. Genes commonly expressed in all three tissue types were also observed. These profilings might provide better fundamental understanding of insulin resistance and development of type 2 diabetes.

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Reactive oxygen species (ROS), such as superoxide anions and hydroxyl radicals, are associated with carcinogenesis and other pathophysiological conditions. Therefore, elimination or inactivation of ROS or inhibition of their excess generation may be beneficial in terms of reducing the risk for cancer and other diseases. Ganoderma lucidum has been used in traditional oriental medicine and has potential antiinflammatory and antioxidant activities. In the present study, we tested the amino-polysaccharide fraction (designated as 'G009') from Ganoderma lucidum for the ability to protect against oxidative damage induced by ROS. G009 significantly inhibited iron-induced lipid peroxidation in rat brain homogenates and showed a dose-dependent inactivation of hydroxyl radicals and superoxide anions. It also reduced strand breakage in phiX174 supercoiled DNA caused by UV-induced photolysis of hydrogen peroxide and attenuated phorbol ester-induced generation of superoxide anions in differentiated human promyelocytic leukaemia (HL-60) cells. These findings suggest that G009 from Ganoderma lucidum possesses chemopreventive potential.