title: Prolonged culture in low glucose induces apoptosis of rat pancreatic beta-cells through induction of c-myc.
abstract: Prolonged culture in low-glucose concentrations (</=5mM) induces apoptosis in pancreatic beta-cells by a poorly defined mechanism. We now show that, in both purified rat beta-cells and isolated rat islets, culture in the presence of 3 or 5mM (G3-G5) instead of 10mM glucose (G10) induces a large increase in c-myc expression before onset of a caspase-dependent apoptosis. These effects were prevented by addition of leucine and glutamine to G3 and G5, and were mimicked by addition of the mitochondrial poison azide to G10. In contrast, inhibition of Ca(2+) influx and insulin secretion with diazoxide under control conditions did not stimulate islet c-myc expression nor beta-cell apoptosis. In rat beta-cells, adenovirus-mediated c-myc overexpression increased their rate of apoptosis, whereas antisense-c-myc expression reduced low-glucose-induced apoptosis by approximately 50%. In the insulin producing MIN6 cell line, apoptosis induction by either low glucose or an activator of AMP-activated protein kinase (AMPK) was associated with c-myc mRNA and protein upregulation. In conclusion, stimulation of beta-cell apoptosis by prolonged culture at low glucose partly results from early and sustained induction of beta-cell c-myc expression. These effects may be due to sustained restriction in nutrient-derived metabolic signals.
authors.affiliation: Diabetes Research Center, Brussels Free University VUB, Brussels, Belgium. mvdcaste@vub.ac.be
authors.forename: Mark
authors.initials: M
authors.lastname: Van de Casteele
authors.forename: Benjamin Ate
authors.initials: BA
authors.lastname: Kefas
authors.forename: Ying
authors.initials: Y
authors.lastname: Cai
authors.forename: Harry
authors.initials: H
authors.lastname: Heimberg
authors.forename: Donald K
authors.initials: DK
authors.lastname: Scott
authors.forename: Jean Claude
authors.initials: JC
authors.lastname: Henquin
authors.forename: Daniël
authors.initials: D
authors.lastname: Pipeleers
authors.forename: Jean Christophe
authors.initials: JC
authors.lastname: Jonas
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D018929:Cell Culture Techniques / Q000379:methods; D002460:Cell Line; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D005973:Glutamine / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D007930:Leucine / Q000494:pharmacology; D051379:Mice; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D051381:Rats
chemical_list: D007328:Insulin; D016271:Proto-Oncogene Proteins c-myc; D005973:Glutamine; D007930:Leucine; D005947:Glucose