Exposure to Chronic High Glucose Induces β-Cell Apoptosis Through Decreased Interaction of Glucokinase With Mitochondria

Abstract

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

Role of uncoupling protein UCP2 in cell-mediated immunity: How macrophage-mediated insulitis is accelerated in a model of autoimmune diabetes

“…In type 1 diabetes, the role of mitochondria has mainly been of interest in cytokine-induced ␤-cell apoptosis (26,27). Whereas the role of UCP2 in type 2 diabetes and autoimmunity is well investigated (1, 2, 6, 7), our manuscript reports the importance of a mitochondrial protein, UCP2, in autoimmune diabetes by using the MLDS murine model for immune-mediated diabetes (12).…”

Chronic treatment with a glucokinase activator delays the onset of hyperglycaemia and preserves beta cell mass in the Zucker diabetic fatty rat

“…Various lines of indirect evidence suggest that pharmacological interventions that augment glucokinase activity may favour mechanisms that slow or prevent beta cell loss [22,23] or promote beta cell proliferation in vivo [3,[24][25][26][27]. The present experiments were undertaken to address an ongoing need for data to test and shed further light on this hypothesis.…”

Anti-apoptotic effects of silk fibroin hydrolysate in RIN5F cell on high glucose condition

“…Also, hyperglycemia induces the generation of ROS and triggers pancreatic β-cell apoptosis (Robertson et al 2003;Kim et al 2005;Ortega-Camarillo et al 2006;Jonas et al 2009). Therefore, prevention of pancreatic β-cell apoptosis induced by hyperglycemia is an important therapeutic issue for diabetic and metabolic disease patients.…”

“…We subsequently asked how SFH maintains pancreatic β-cell mass under hyperglycemic conditions. Exposure to high glucose conditions reduces pancreatic β-cell viability (Kim et al 2005;Robertson et al 2003;Jonas et al 2009). Thus, the effects of SFH on high glucose conditions were investigated in RIN5F cells.…”

“…High glucose conditions have been implicated in the death of pancreatic β-cells (Efanova et al 1998;Kim et al 2005;Ortega-Camarillo et al 2006). To investigate the potential anti-apoptotic effect of SFH against high glucose conditions in vitro, we measured the percentage of apoptotic cells using flow cytometry analysis (FACS, Figure 2).…”