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.
Ling
Zhidong
Z
Diabetes Research Center, Brussels Free University-Vrije Universiteit Brussels, Laarbeeklaan 103, B-1090 Brussels, Belgium.
Wang
Qidi
Q
Stangé
Geert
G
In't Veld
Peter
P
Pipeleers
Daniel
D
D000818:Animals; D002118:Calcium / Q000378:metabolism; D015550:Cell Degranulation / Q000187:drug effects; D004334:Drug Administration Schedule; D005905:Glyburide / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000096:biosynthesis*; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051381:Rats; D017208:Rats, Wistar
D007004:Hypoglycemic Agents; D007328:Insulin; D005905:Glyburide; D002118:Calcium