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1Unit of Endocrinology and Metabolism and 2Service of Pathology, University of Louvain Faculty of Medicine, B-1200 Brussels, Belgium
Submitted 22 September 2003 ; accepted in final form 16 April 2004
Chronic hyperglycemia has been shown to induce either a lack of response or an increased sensitivity to glucose in pancreatic 
-cells. We reinvestigated this controversial issue in a single experimental model by culturing rat islets for 1 wk in 10 or 30 mmol/l glucose (G10, Controls; or G30, High-glucose islets) before testing the effect of stepwise glucose stimulation from G0.5 to G20 on key -cell stimulus-secretion coupling events. Compared with Controls, the glucose sensitivity of High-glucose islets was markedly increased, leading to maximal stimulation of oxidative metabolism and both triggering and amplifying pathways of insulin secretion in G6 rather than G20, hence to loss of glucose effect above G6. This enhanced glucose sensitivity occurred despite an approximately twofold increase in islet uncoupling protein 2 mRNA expression. Besides this increased glucose sensitivity, the maximal glucose stimulation of insulin secretion in High-glucose islets was reduced by 
50%, proportionally to the reduction of insulin content. In High-glucose islets, changes in 45Ca2+ influx induced by glucose and diazoxide were qualitatively similar but quantitatively smaller than in Control islets and, paradoxically, did not lead to detectable changes in the intracellular Ca2+ concentration measured by microspectrofluorimetry (fura PE 3). In conclusion, after 1 wk of culture in G30, the loss of glucose stimulation of insulin secretion in the physiological range of glucose concentrations (G5–G10) results from the combination of an increased sensitivity to glucose of both triggering and amplifying pathways of insulin secretion and an 50% reduction in the maximal glucose stimulation of insulin secretion.
pancreatic -cell; cytosolic calcium concentration; mitochondrial activity; glucose toxicity
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