Survival and function of insulin-secreting pancreatic beta-cells are markedly altered by changes in nutrient availability. In vitro, culture in 10 rather than 2mM glucose improves rodent beta-cell survival and function whereas glucose concentrations above 10mM are deleterious. The purpose of this study was to identify the mechanisms of such beta-cell plasticity; we tested the effects of a 18h culture at 2, 5, 10 and 30mM glucose on the transcriptome of rat islets precultured for 1 week at 10mM glucose (Affymetrix Rat 230.2 arrays).

Identify genes and pathways in rat pancreatic islets affected by prolonged exposure to high and low levels of glucose.

Microarrays analyses were performed on cultured rat islets using theAffymetrix GeneChip Rat Genome 230 2.0 Array. Islets were precultured in 10 mM glucose for 1 week to remove the stress effects of isolation and adaptation to culture and then exposed to 2mM, 5mM, 10 mM, and 30 mM glucose for 18 hours to see effects on beta cell function (glucose sensitivity, insulin secretion, Ca++ levels) but not yet noticeably affect cell survival.

About 5000 probe sets were up- or downregulated more than 1.4 fold between glucose conditions. Hormone transcripts were well represented while acinar and ductal cell transcripts were absent indicating that the observed effects were not due to contaminating cells. Genes most affected by glucose include those known to be strongly induced by high glucose and contribute to beta cell glucotoxicity (Aldob, Txnip, Crem, Fos). Other genes most affected are involved in integrated stress response (Dbp, Ddit3, Trib3), apoptosis (Fas), and oxidative stress (Mt1a, Hmox1). Transcription factors, Srebp1 and Srebp2, involved in fatty acid metabolism were also affected.

Eighteen distinct mRNA profiles of glucose-induced changes were identified demonstrating that glucose effects on islet gene expression are complex.

• insulin secretion: 550, 930, 990, 1030, 1050, 2160, 3042, 3546, 3650, 3980,
• stress and apoptosis in islets/ beta cells: 751, 2000, 2001, 2020, 2021, 2301, 2904, 3244, 3650, 3975, 3977, 3979, 3980,