title: Stevioside counteracts the glyburide-induced desensitization of the pancreatic beta-cell function in mice: studies in vitro.
abstract: The sulfonylurea glyburide (GB) is one of the most frequently used drugs in diabetes treatment. Long-term pretreatment with GB causes elevated basal insulin secretion (BIS) and decreased glucose-stimulated insulin secretion (GSIS). These characteristics may play an important role for the development of hypoglycemia and secondary failure. Stevioside (SVS), a substance extracted from leaves of Stevia rebaudiana Bertoni, enhances GSIS but not BIS. The aim of the present study was to clarify whether 24-hour exposure of isolated mouse islets to GB causes dose-dependent decrease in the GSIS and whether it is possible to counteract this desensitization by SVS. We also tested the impact of the incretin glucagon-like peptide-1 (GLP-1) on the GB-induced desensitization. After 24-hour preincubation with GB in combination with SVS or GLP-1, we measured the basal and glucose-stimulated insulin responses and the total islet insulin content. We also determined the fold change in gene expression of pancreatic and duodenal homeobox 1 and glucose transporter isoform 2. After 24-hour preincubation in 11.1 mmol/L glucose, GB (10(-11)-10(-3) mol/L) caused a dose-dependent decrease in GSIS (16.7 mmol/L glucose) (P < .001). GB (10(-7) mol/L) pretreatment elevated BIS, but neither SVS (10(-7) mol/L) nor GLP-1 (10(-7) mol/L) could reverse this. Interestingly, the GB-induced desensitization of GSIS was counteracted by both SVS (P < .05) and GLP-1 (P < .05). SVS reversed the decrease in insulin content caused by GB pretreatment (P < .05). GB pretreatment did not change gene expression of pancreatic and duodenal homeobox 1 nor glucose transporter isoform 2, whereas SVS significantly up-regulated the expression of both genes by more than 2-fold (P < .05). Our results showed that SVS in combination with GB did not reverse GB-induced increase in BIS, whereas both SVS and GLP-1 counteracted GB-induced desensitization of GSIS. SVS is able to counteract the desensitizing effects of GB and may be a putative new drug candidate for the treatment of type 2 diabetes mellitus.
authors.affiliation: Department of Endocrinology and Metabolism C, Aarhus Sygehus THG, Aarhus University Hospital, DK-8000 Aarhus C, Denmark. jianguo.chen@ki.au.dk
authors.forename: Jianguo
authors.initials: J
authors.lastname: Chen
authors.forename: Per Bendix
authors.initials: PB
authors.lastname: Jeppesen
authors.forename: Iver
authors.initials: I
authors.lastname: Nordentoft
authors.forename: Kjeld
authors.initials: K
authors.lastname: Hermansen
mesh_terms: D000818:Animals; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D045786:Diterpenes, Kaurane / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology; D051273:Glucose Transporter Type 2 / Q000235:genetics; D005960:Glucosides / Q000494:pharmacology*; D005905:Glyburide / Q000494:pharmacology*; D018398:Homeodomain Proteins / Q000235:genetics; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D015534:Trans-Activators / Q000235:genetics
chemical_list: D045786:Diterpenes, Kaurane; D051273:Glucose Transporter Type 2; D005960:Glucosides; D018398:Homeodomain Proteins; D007004:Hypoglycemic Agents; D007328:Insulin; C495682:Slc2a2 protein, mouse; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; C012043:stevioside; D052216:Glucagon-Like Peptide 1; D005905:Glyburide; D004121:Dimethyl Sulfoxide