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1 Unit of Endocrinology and Metabolism, University of Louvain Faculty of Medicine, Brussels, Belgium
2 Service of Pathology, University of Louvain Faculty of Medicine, Brussels, Belgium
* To whom correspondence should be addressed. E-mail: jonas{at}endo.ucl.ac.be.
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 one week in 10 or 30 mmol.L-1 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 a ~2 fold increase in islet UCP2 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 (furaPE3). In conclusion, after one week culture in
G30, the loss of glucose stimulation of insulin secretion in the physiological range of glucose
concentrations (G5 to 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.
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