Glibenclamide treatment recruits beta-cell subpopulation into elevated and sustained basal insulin synthetic activity.

Use of sulfonylureas in diabetes treatment is based on their insulin-releasing effect on pancreatic beta-cells. Prolonged action is known to degranulate beta-cells, but functional consequences have not been examined at the cellular level. This study investigates influences of in vivo (48-h) and in vitro (24-h) glibenclamide treatment on the functional state of the beta-cell population. Both conditions decreased cellular insulin content by >50% and caused an elevated basal insulin biosynthetic activity that was maintained for at least 24 h after drug removal. Glibenclamide stimulation of basal insulin synthesis was not achieved after a 2-h exposure; it required a calcium-dependent translational activity and involved an increase in the percent activated beta-cells (50% after glibenclamide pretreatment vs. 8% in control cells). The glibenclamide-activated beta-cell subpopulation corresponded to the degranulated beta-cell subpopulation that was isolated by fluorescence-activated cell sorter on the basis of lower cellular sideward scatter. Glibenclamide pretreatment did not alter cellular rates of glucose oxidation but sensitized beta-cells to glucose-induced changes in metabolic redox and insulin synthesis and release. In conclusion, chronic exposure to glibenclamide results in degranulation of a subpopulation of beta-cells, which maintain an elevated protein and insulin synthetic activity irrespective of the presence of the drug and of glucose. Our study demonstrates that the in situ beta-cell population also exhibits a functional heterogeneity that can vary with drug treatment. Glibenclamide induces degranulated beta-cells with a sustained elevated basal activity that might increase the risk for hypoglycemic episodes.