Journal
DIABETOLOGIA
Volume 52, Issue 3, Pages 463-476Publisher
SPRINGER
DOI: 10.1007/s00125-008-1245-z
Keywords
Apoptosis; Beta cell; Cluster analysis; Endoplasmic reticulum stress response; Phenotypic plasticity
Categories
Funding
- Fonds de la Recherche Scientifique Medicale (Belgium) [3.4506.05]
- General Direction of Scientific Research of the French Community of Belgium [ARC 05/10-328]
- Interuniversity Poles of Attraction Program [P6/42]
- GOA [2004-11]
- Centre of Excellence SymBioSys [EF/05/007]
- Fonds de la Recherche Scientifique-FNRS (Belgium)
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Survival and function of insulin-secreting pancreatic beta cells are markedly altered by changes in nutrient availability. In vitro, culture in 10 rather than 2 mmol/l glucose improves rodent beta cell survival and function, whereas glucose concentrations above 10 mmol/l are deleterious. To identify the mechanisms of such beta cell plasticity, we tested the effects of 18 h culture at 2, 5, 10 and 30 mmol/l glucose on the transcriptome of rat islets pre-cultured for 1 week at 10 mmol/l glucose using Affymetrix Rat 230 2.0 arrays. Culture in either 2-5 or 30 mmol/l instead of 10 mmol/l glucose markedly impaired beta cell function, while little affecting cell survival. Of about 16,000 probe-sets reliably detected in islets, some 5,000 were significantly up- or downregulated at least 1.4-fold by glucose. Analysis of these probe-sets with GeneCluster software identified ten mRNA profiles with unidirectional up- or downregulation between 2 and 10, 2 and 30, 5 and 10, 5 and 30 or 10 and 30 mmol/l glucose. It also identified eight complex V-shaped or inverse V-shaped profiles with a nadir or peak level of expression in 5 or 10 mmol/l glucose. Analysis of genes belonging to these various clusters using Onto-express and GenMAPP software revealed several signalling and metabolic pathways that may contribute to induction of beta cell dysfunction and apoptosis after culture in low- or high- vs intermediate-glucose concentration. We have identified 18 distinct mRNA profiles of glucose-induced changes in islet gene mRNA levels that should help understand the mechanisms by which glucose affects beta cell survival and function under states of chronic hypo- or hyperglycaemia.
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