In the adult GK rat, a spontaneous model of type 2 diabetes, total pancreatic β-cell number is decreased by 60%. This alteration cannot be ascribed to increased β-cell apoptosis but is related to decreased β-cell replication. Moreover, the adult GK pancreas exhibits large islets disrupted by connective tissue. Our objective was therefore to identify genes possibly involved in the β-cell growth phenotype in adult diabetic GK rat. Differential gene expression was evaluated in islets of adult diabetic GK and normal Wistar (W) rats by high density oligonucleotide microarray. Total RNA was extracted from 16 week-old W and GK islets. Biotin-labeled cRNA probes were synthesized and hybridized to Affymetrix RG-U34A oligonucleotide microarrays containing approximately 7,000 rat genes. The arrays were scanned and expression values for the genes were determined using Affymetrix Microarray Suite 5.0 and Affymetrix Data Mining Tool 2.0. Expression pattern of reg in GK pancreas was determined by immunohistochemical analysis. No difference in expression levels of genes encoding growth factors for β-cells (GH, IGF1, PDGF, HGF, insulin) and the c-Myc transcription factor was found in Wistar and GK rats. By contrast, several reg-related genes were up-regulated in the GK islets (46-, 12- and 11-fold respectively for reg II, reg I and reg III genes). These results were confirmed by real-time PCR. Expression of several stress genes such as glutathione peroxidase (2.7-fold) , thioredoxine interating protein (5.4-fold) and heat shock protein 70 (2.3-fold) were increased in GK islets. Islets from GK rats also display increased expression of inflammatory genes such as lipocalin 2 (72.8-fold), decorin (4.1-fold) and annexins 1 and 2 genes (8.7- and 2.1-fold). To localize the reg-I protein in pancreas we stained sections of GK and W pancreases. Immunoreactivity was observed only in islets. Reg staining was colocalized with staining for insulin but did not seem restricted to the β-cells.Our data suggest that in GK islets 1) the increased expression of reg family genes whose involvement in β-cell regeneration has been proposed, may be an integral part of the β-cell growth phenotype of GK islets; 2) the lack of increased apoptosis of the β-cells may be related to activation of several stress genes that confer protection against β-cell death; 3) the increased expression of cytokine genes could be related to a local inflammatory response in GK islets; 4) the local inflammatory gene overexpression together with the cytokine environment in GK islets may have an influence on reg gene expression. Our working hypothesis is, that these expression changes reported for the first time in GK islets could represent an acquired adaptation in response to chronic hyperglycemia (glucotoxicity). To learn what genes are more directly involved in the pathology of the GK rats, we are currently analyzing the gene expression profile in young prediabetic GK rats